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Skin resident T cellsImplications for immune homeostasis and diseasedos Reis Matos, T.

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Citation for published version (APA):dos Reis Matos, T. (2019). Skin resident T cells: Implications for immune homeostasis and disease.

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Download date: 22 Feb 2021

Summary / Nederlandstalige samenvatting List of Abbreviations

List of contributing authors List of publications

PhD Portfolio Curriculum Vitae

Acknowledgements

SUMMARY

This thesis focuses on skin resident T cells and how these cells are crucial to maintain healthy tissue. TRM cells are key players in keeping the cutaneous immune homeostasis, but when aberrantly activated, skin-located TRM cells also have a profound role in various skin disorders (chapter 1). Part I elaborates on the origin, differentiation and migration of resident T cells. In chapter 2, we highlight the key article of Bos et al. (1987), which confirmed once and for all, that lymphocytes are constantly present in healthy skin. This crucial discovery contributed to a new generation of cutaneous immunology research, including a greater appreciation for skin T cells. In chapter 3 we examine how all circulating T cell subsets can give rise to TRM cells after entering the skin. Although TCM were the most effective precursors, we observed that all circulating T cell subsets can generate TRM cells. Chapter 4 further accentuates how distinct circulatory lymphocyte subsets can provide tissue immunosurveillance. Both human TCM and TEM, express peripheral tissue-homing receptors, and they are found in several healthy human tissues, have impressive effector functions, and can act alone to induce skin inflammation. It supports a novel role for human TCM in primary immunosurveillance of peripheral tissues. Acknowledging that different subclasses of lymphocytes are present within peripheral tissues and mediate immunosurveillance, chapter 5 provides a detailed characterization of the relative proportions and functional activities of resident versus recirculating T cells in human skin. This study shows that human skin is protected by four functionally distinct populations of T cells, two resident (TRM CD103+ or CD103-) and two recirculating (TCM and TMM), with differing territories of migration (epidermis versus dermis) and distinct functional activities. In chapter 6 we prove that skin TRM cells are mobile in human and mouse epidermis. CD8+ TRM patrol the skin by migrating through the papillary dermis and through the epidermis, below sessile Langerhans cells. Part II studied the role of TRM cells in diverse skin diseases, such as in psoriasis, graft-versus-host-disease and vitiligo. Chapter 7 explores the contribution of resident T cell populations in psoriasis. It shows IL-17 producing αβ T cell clones with psoriasis-specific antigen receptors present in clinically resolved psoriatic skin lesions. These oligoclonal populations of T cells may represent the disease initiating pathogenic T cells in psoriasis and lasting control of this disease requires suppression of these resident T cell populations. Chapter 8 analyzes the role of interleukin-9 as an early amplifier of inflammation and its influence on TRM cells. CD4+ IL-9 producing T cells were as frequent as IL-17 producing T cells in human psoriasis but most IL-9 was produced by non-TH17 cells.

387

SUMMARY

This thesis focuses on skin resident T cells and how these cells are crucial to maintain healthy tissue. TRM cells are key players in keeping the cutaneous immune homeostasis, but when aberrantly activated, skin-located TRM cells also have a profound role in various skin disorders (chapter 1). Part I elaborates on the origin, differentiation and migration of resident T cells. In chapter 2, we highlight the key article of Bos et al. (1987), which confirmed once and for all, that lymphocytes are constantly present in healthy skin. This crucial discovery contributed to a new generation of cutaneous immunology research, including a greater appreciation for skin T cells. In chapter 3 we examine how all circulating T cell subsets can give rise to TRM cells after entering the skin. Although TCM were the most effective precursors, we observed that all circulating T cell subsets can generate TRM cells. Chapter 4 further accentuates how distinct circulatory lymphocyte subsets can provide tissue immunosurveillance. Both human TCM and TEM, express peripheral tissue-homing receptors, and they are found in several healthy human tissues, have impressive effector functions, and can act alone to induce skin inflammation. It supports a novel role for human TCM in primary immunosurveillance of peripheral tissues. Acknowledging that different subclasses of lymphocytes are present within peripheral tissues and mediate immunosurveillance, chapter 5 provides a detailed characterization of the relative proportions and functional activities of resident versus recirculating T cells in human skin. This study shows that human skin is protected by four functionally distinct populations of T cells, two resident (TRM CD103+ or CD103-) and two recirculating (TCM and TMM), with differing territories of migration (epidermis versus dermis) and distinct functional activities. In chapter 6 we prove that skin TRM cells are mobile in human and mouse epidermis. CD8+ TRM patrol the skin by migrating through the papillary dermis and through the epidermis, below sessile Langerhans cells. Part II studied the role of TRM cells in diverse skin diseases, such as in psoriasis, graft-versus-host-disease and vitiligo. Chapter 7 explores the contribution of resident T cell populations in psoriasis. It shows IL-17 producing αβ T cell clones with psoriasis-specific antigen receptors present in clinically resolved psoriatic skin lesions. These oligoclonal populations of T cells may represent the disease initiating pathogenic T cells in psoriasis and lasting control of this disease requires suppression of these resident T cell populations. Chapter 8 analyzes the role of interleukin-9 as an early amplifier of inflammation and its influence on TRM cells. CD4+ IL-9 producing T cells were as frequent as IL-17 producing T cells in human psoriasis but most IL-9 was produced by non-TH17 cells.

388

IL-9 acted early on TRM to enhance pathogenic cytokine production, consistent with a role for IL-9 as an early amplifier of inflammation in diverse inflammatory states. Chapter 9 investigates the role of TRM cells in Graft-versus-Host-Disease (GvHD). GvHD is a major cause of illness and death in patients following hematopoietic stem cell transplantation. We show that skin resident T cells when challenged by allogeneic donor-derived antigen presenting cells, proliferate and produce cytokines known to participate in the pathogenesis of GvHD. It suggests that TRM depletion strategies may be helpful in reducing GvHD. Chapter 10 describes how skin-located TRM cells contribute to vitiligo and melanoma, as well as their potential as therapeutic targets in both diseases. The presence of autoreactive TRM cells in lesional vitiligo skin and mouse models indicate that targeting these cells might be effective as a durable treatment strategy for vitiligo. Conversely, the induction of melanoma-reactive TRM cells is needed to achieve effective protection against tumor growth. Part III reviews the value of phototherapy for TRM-associated diseases, such as psoriasis and vitiligo. Chapter 11 introduces phototherapy as perhaps the most ancient form of treatment in dermatology, being responsible for the management of a wide variety of skin diseases. It remains an extremely effective, safe and broadly used form of treatment. The ultraviolet radiation (UVR), from either the sun or artificial light sources, has a profound immunomodulatory effect. Chapter 12 provides an overview of the immunological mechanisms by which ultraviolet radiation is responsible for the therapeutic effects of phototherapy. UVR mostly induces the innate while suppresses the adaptive immune system, leading to both local and systemic effects. It is antigen-specific, acts on both effector and regulatory T cells, alters antigen-presenting cell function and induces the secretion of cytokines and soluble mediators. UVR can have a beneficial biological impact on skin, but is also the most significant environmental risk factor for skin cancer development. Chapter 13 describes the molecular and cellular mechanisms that are currently recognized as contributing to photocarcinogenesis. Chapter 14 elaborates on the existing literature of four main ultraviolet B (UVB) modalities of phototherapy in the management of psoriasis: heliotherapy, broadband UVB, narrowband UVB (NBUVB) and excimer laser and lamp. It provides an updated comprehensive overview of UVB phototherapy for psoriasis to help physicians optimize their choice of modality and dosing regimen to ensure optimal outcomes for psoriasis patients. Phototherapy was also the first available treatment for vitiligo as it remaining the safest, most efficient and frequently used therapy. NBUVB is capable of stimulating repigmentation and induce disease-regression. Part IV shares cutting-edge technologies used in this thesis, such as mass cytometry and high-throughput TCR sequencing. Chapter 15 discusses the challenge of effective communication among scientists or physicians. It introduces the research techniques

made simple (RTMS) manuscripts as fundamental tools to share research knowledge and the vocabulary necessary to an effective communication among clinicians and researchers. In chapter 16 we review key experimental methods for mass cytometry by time of flight (CyTOF). Cutting-edge CyTOF can profoundly impact our scientific knowledge. However, the success of mass cytometry experiments depends on fully understanding the methods and how to control for variations when making comparisons between samples. The subsequent challenge of examining, visualizing, and presenting mass cytometry data has motivated continuous development of dimensionality reduction methods. Chapter 17 reviews some frequently used and accessible mass cytometry data analysis tools, including Principal Component Analysis (PCA), Spanning-tree Progression Analysis of Density-normalized Events (SPADE), t-distributed stochastic neighbor embedding (t-SNE)-based visualization (viSNE) and Automatic Classification of Cellular Expression by Non-linear Stochastic Embedding (ACCENSE), and Cluster Identification, Characterization, and Regression (CITRUS). High-throughput sequencing (HTS) of the T-cell receptor (TCR) is another novel rapidly advancing immunological technique that allows sensitive and accurate identification and quantification of every distinct T-cell clone present within any biological sample. Chapter 18 elaborates on the methodology, advances, and limitations of HTS of the TCR, and describe emerging applications of this technique in the field of investigative dermatology. We recapitulate the chapters of part IV through a quiz in chapter 19. It highlights the robustness of the RTMS manuscripts, which included not only the manuscript but also bullet points highlighting the pros and cons, examples of how to use the technique, a quiz and a PowerPoint presentation allowing readers to promptly share and teach the techniques (available online as supplemental material). Lastly, in chapter 20 we discuss the results and present final conclusion. Chapter 21 elaborates on future perspectives: using skin TRM cells in therapeutic and preventive medicine.

389

IL-9 acted early on TRM to enhance pathogenic cytokine production, consistent with a role for IL-9 as an early amplifier of inflammation in diverse inflammatory states. Chapter 9 investigates the role of TRM cells in Graft-versus-Host-Disease (GvHD). GvHD is a major cause of illness and death in patients following hematopoietic stem cell transplantation. We show that skin resident T cells when challenged by allogeneic donor-derived antigen presenting cells, proliferate and produce cytokines known to participate in the pathogenesis of GvHD. It suggests that TRM depletion strategies may be helpful in reducing GvHD. Chapter 10 describes how skin-located TRM cells contribute to vitiligo and melanoma, as well as their potential as therapeutic targets in both diseases. The presence of autoreactive TRM cells in lesional vitiligo skin and mouse models indicate that targeting these cells might be effective as a durable treatment strategy for vitiligo. Conversely, the induction of melanoma-reactive TRM cells is needed to achieve effective protection against tumor growth. Part III reviews the value of phototherapy for TRM-associated diseases, such as psoriasis and vitiligo. Chapter 11 introduces phototherapy as perhaps the most ancient form of treatment in dermatology, being responsible for the management of a wide variety of skin diseases. It remains an extremely effective, safe and broadly used form of treatment. The ultraviolet radiation (UVR), from either the sun or artificial light sources, has a profound immunomodulatory effect. Chapter 12 provides an overview of the immunological mechanisms by which ultraviolet radiation is responsible for the therapeutic effects of phototherapy. UVR mostly induces the innate while suppresses the adaptive immune system, leading to both local and systemic effects. It is antigen-specific, acts on both effector and regulatory T cells, alters antigen-presenting cell function and induces the secretion of cytokines and soluble mediators. UVR can have a beneficial biological impact on skin, but is also the most significant environmental risk factor for skin cancer development. Chapter 13 describes the molecular and cellular mechanisms that are currently recognized as contributing to photocarcinogenesis. Chapter 14 elaborates on the existing literature of four main ultraviolet B (UVB) modalities of phototherapy in the management of psoriasis: heliotherapy, broadband UVB, narrowband UVB (NBUVB) and excimer laser and lamp. It provides an updated comprehensive overview of UVB phototherapy for psoriasis to help physicians optimize their choice of modality and dosing regimen to ensure optimal outcomes for psoriasis patients. Phototherapy was also the first available treatment for vitiligo as it remaining the safest, most efficient and frequently used therapy. NBUVB is capable of stimulating repigmentation and induce disease-regression. Part IV shares cutting-edge technologies used in this thesis, such as mass cytometry and high-throughput TCR sequencing. Chapter 15 discusses the challenge of effective communication among scientists or physicians. It introduces the research techniques

made simple (RTMS) manuscripts as fundamental tools to share research knowledge and the vocabulary necessary to an effective communication among clinicians and researchers. In chapter 16 we review key experimental methods for mass cytometry by time of flight (CyTOF). Cutting-edge CyTOF can profoundly impact our scientific knowledge. However, the success of mass cytometry experiments depends on fully understanding the methods and how to control for variations when making comparisons between samples. The subsequent challenge of examining, visualizing, and presenting mass cytometry data has motivated continuous development of dimensionality reduction methods. Chapter 17 reviews some frequently used and accessible mass cytometry data analysis tools, including Principal Component Analysis (PCA), Spanning-tree Progression Analysis of Density-normalized Events (SPADE), t-distributed stochastic neighbor embedding (t-SNE)-based visualization (viSNE) and Automatic Classification of Cellular Expression by Non-linear Stochastic Embedding (ACCENSE), and Cluster Identification, Characterization, and Regression (CITRUS). High-throughput sequencing (HTS) of the T-cell receptor (TCR) is another novel rapidly advancing immunological technique that allows sensitive and accurate identification and quantification of every distinct T-cell clone present within any biological sample. Chapter 18 elaborates on the methodology, advances, and limitations of HTS of the TCR, and describe emerging applications of this technique in the field of investigative dermatology. We recapitulate the chapters of part IV through a quiz in chapter 19. It highlights the robustness of the RTMS manuscripts, which included not only the manuscript but also bullet points highlighting the pros and cons, examples of how to use the technique, a quiz and a PowerPoint presentation allowing readers to promptly share and teach the techniques (available online as supplemental material). Lastly, in chapter 20 we discuss the results and present final conclusion. Chapter 21 elaborates on future perspectives: using skin TRM cells in therapeutic and preventive medicine.

NEDERLANDSE SAMENVATTING

In dit proefschrift staan zogenaamde “tissue resident memory T cells” oftewel weefselresidente T-geheugencellen (afgekort tot TRM-cellen) centraal en is beschreven hoe deze cellen cruciaal zijn voor het behoud van gezond weefsel. In de huid gelokaliseerde TRM-cellen zijn niet alleen belangrijke spelers bij het in stand houden van de cutane immuunhomeostase, maar kunnen wanneer ze afwijkende activatie signalen ontvangen ook een essentiële rol spelen bij verschillende huidaandoeningen (hoofdstuk 1). Deel I gaat dieper in op de oorsprong, differentiatie en migratie van TRM-cellen. In hoofdstuk 2 wordt het sleutelartikel van Bos et al. (1987) besproken, waarin voor eens en voor altijd bevestigd werd dat lymfocyten permanent aanwezig zijn in een gezonde huid. Deze cruciale ontdekking heeft bijgedragen aan een nieuwe generatie van immunologisch onderzoek in de huid, waaronder een grotere waardering voor T-cellen in de huid. In hoofdstuk 3 is onderzocht hoe TRM-cellen kunnen ontstaan uit verschillende circulerende T-cel subsets die naar de huid kunnen migreren. Hoewel de zogenaamde centrale T-geheugencellen (TCM) de meest effectieve voorlopers waren bleken TRM-cellen ook te kunnen ontstaan uit andere circulerende T-cel subsets, hetgeen de enorme overmaat en flexibiliteit van T-cellen illustreert om te reageren op ziekteverwekkers in perifere weefsels. Na te hebben vastgesteld dat TRM-cellen kunnen worden gegenereerd uit alle subtypen circulerende T-cellen, wordt in hoofdstuk 4 verder benadrukt hoe afzonderlijke lymfocytensubtypen in de bloedcirculatie een rol kunnen spelen in de bewaking van weefsel. Humane TCM en effector T-geheugencellen (TEM) brengen homing-receptoren voor perifeer weefsel tot expressie, zijn beiden te vinden in verschillende gezonde menselijke weefsels, hebben indrukwekkende effector functies en kunnen zelfstandig werken om een huidontsteking te induceren. Dit ondersteunt een nieuwe rol voor humane TCM bij primaire immunosurveillance van perifere weefsels. Met als uitgangspunt dat er verschillende subklassen van lymfocyten aanwezig zijn in perifere weefsels en immunosurveillance uitvoeren, geeft hoofdstuk 5 een gedetailleerde beschrijving van de relatieve verhoudingen en functionele activiteiten van residente versus recirculerende T-cellen in de menselijke huid. Deze studie toont aan dat de menselijke huid wordt beschermd door vier functioneel verschillende populaties van T-cellen: twee residente (TRM CD103+ of CD103‒) en twee recirculerende (TCM en TMM) T-cel subsets, met verschillende migratie-eigenschappen (epidermis versus dermis) en verschillende functionele activiteiten. In hoofdstuk 6 bewijzen we dat epidermale TRM-cellen mobiel zijn, zowel bij de mens als bij de muis. CD8+ TRM patrouilleren door de huid door voortdurend te migreren door de papillaire dermis en epidermis, net onder het niveau van sessiele Langerhans cellen.

391

NEDERLANDSE SAMENVATTING

In dit proefschrift staan zogenaamde “tissue resident memory T cells” oftewel weefselresidente T-geheugencellen (afgekort tot TRM-cellen) centraal en is beschreven hoe deze cellen cruciaal zijn voor het behoud van gezond weefsel. In de huid gelokaliseerde TRM-cellen zijn niet alleen belangrijke spelers bij het in stand houden van de cutane immuunhomeostase, maar kunnen wanneer ze afwijkende activatie signalen ontvangen ook een essentiële rol spelen bij verschillende huidaandoeningen (hoofdstuk 1). Deel I gaat dieper in op de oorsprong, differentiatie en migratie van TRM-cellen. In hoofdstuk 2 wordt het sleutelartikel van Bos et al. (1987) besproken, waarin voor eens en voor altijd bevestigd werd dat lymfocyten permanent aanwezig zijn in een gezonde huid. Deze cruciale ontdekking heeft bijgedragen aan een nieuwe generatie van immunologisch onderzoek in de huid, waaronder een grotere waardering voor T-cellen in de huid. In hoofdstuk 3 is onderzocht hoe TRM-cellen kunnen ontstaan uit verschillende circulerende T-cel subsets die naar de huid kunnen migreren. Hoewel de zogenaamde centrale T-geheugencellen (TCM) de meest effectieve voorlopers waren bleken TRM-cellen ook te kunnen ontstaan uit andere circulerende T-cel subsets, hetgeen de enorme overmaat en flexibiliteit van T-cellen illustreert om te reageren op ziekteverwekkers in perifere weefsels. Na te hebben vastgesteld dat TRM-cellen kunnen worden gegenereerd uit alle subtypen circulerende T-cellen, wordt in hoofdstuk 4 verder benadrukt hoe afzonderlijke lymfocytensubtypen in de bloedcirculatie een rol kunnen spelen in de bewaking van weefsel. Humane TCM en effector T-geheugencellen (TEM) brengen homing-receptoren voor perifeer weefsel tot expressie, zijn beiden te vinden in verschillende gezonde menselijke weefsels, hebben indrukwekkende effector functies en kunnen zelfstandig werken om een huidontsteking te induceren. Dit ondersteunt een nieuwe rol voor humane TCM bij primaire immunosurveillance van perifere weefsels. Met als uitgangspunt dat er verschillende subklassen van lymfocyten aanwezig zijn in perifere weefsels en immunosurveillance uitvoeren, geeft hoofdstuk 5 een gedetailleerde beschrijving van de relatieve verhoudingen en functionele activiteiten van residente versus recirculerende T-cellen in de menselijke huid. Deze studie toont aan dat de menselijke huid wordt beschermd door vier functioneel verschillende populaties van T-cellen: twee residente (TRM CD103+ of CD103‒) en twee recirculerende (TCM en TMM) T-cel subsets, met verschillende migratie-eigenschappen (epidermis versus dermis) en verschillende functionele activiteiten. In hoofdstuk 6 bewijzen we dat epidermale TRM-cellen mobiel zijn, zowel bij de mens als bij de muis. CD8+ TRM patrouilleren door de huid door voortdurend te migreren door de papillaire dermis en epidermis, net onder het niveau van sessiele Langerhans cellen.

392

In Deel II is de rol van TRM-cellen in diverse huidziekten bestudeerd, bijvoorbeeld bij psoriasis, graft-versus-host-ziekte (GvHD) en vitiligo. In hoofdstuk 7 is de bijdrage van residente T-celpopulaties bij psoriasis onderzocht. Het toont IL-17 producerende αβ T-celklonen met psoriasisspecifieke antigeenreceptoren die aanwezig zijn in klinisch genezen psoriatische huidlaesies. Mogelijk vertegenwoordigen deze oligoklonale T-celpopulaties een groep van ziekte-initiërende pathogene T-cellen bij psoriasis en zou langdurige beheersing van deze ziekte onderdrukking van deze residente T-cel populaties vereisen. Hoofdstuk 8 analyseert de rol van interleukine-9 (IL-9) als een vroege ontstekingsversterker en de invloed ervan op TRM cellen. IL-9 producerende CD4+ T-helpercellen zijn even frequent aanwezig als IL-17 producerende T-helpercellen (TH17 cellen) bij psoriasis, maar het meeste IL-9 werd geproduceerd door niet-TH17 cellen. IL-9 liet vroege effecten op TRM zien om de pathogene cytokineproductie te verbeteren, hetgeen consistent is met een rol voor IL-9 als een vroege ontstekingsversterker in diverse ontstekingsaandoeningen. In hoofdstuk 9 is de rol van TRM-cellen in GvHD onderzocht. GvHD is een belangrijke oorzaak van ziekte en overlijden bij patiënten na hematopoietische stamceltransplantatie. We laten zien dat wanneer TRM-cellen in de huid worden geprikkeld door allogene donorafgeleide antigenpresenterende cellen, TRM-cellen gaan prolifereren en cytokinen produceren waarvan bekend is dat ze deelnemen aan de pathogenese van GvHD. De resultaten suggereren dat TRM-uitputtingsstrategieën nuttig zouden kunnen zijn bij het verminderen van GvHD. Hoofdstuk 10 onderzoekt hoe cutane TRM-cellen bijdragen aan vitiligo en melanoom, evenals hun potentieel als therapeutische doelen in beide ziekten. De aanwezigheid van autoreactieve TRM-cellen in vitiligo laesies en in muismodellen van vitiligo geven aan dat het richten op deze cellen effectief kan zijn als een duurzame behandelingsstrategie voor vitiligo. Omgekeerd is de inductie van melanoom-reactieve TRM-cellen nodig om effectieve bescherming tegen tumorgroei te bereiken. Deel III beschrijft de waarde van fototherapie voor TRM gerelateerde ziekten, zoals psoriasis en vitiligo. Hoofdstuk 11 introduceert fototherapie als misschien wel de oudste vorm van behandeling in de dermatologie, en die wordt toegepast voor het verbeteren van een breed scala aan huidziekten. Het blijft een uiterst effectieve, veilige en algemeen gebruikte vorm van behandeling. De ultraviolette straling (UVR), afkomstig van de zon of kunstmatige lichtbronnen, heeft een krachtig immunomodulerend effect. Hoofdstuk 12 geeft een overzicht van de immunologische mechanismen waarmee ultraviolette straling verantwoordelijk is voor de therapeutische effecten van fototherapie. UVR activeert meestal het aangeboren immuunsysteem, terwijl het adaptieve immuunsysteem wordt onderdrukt, en leidt tot zowel lokale als systemische effecten. Het effect is antigenspecifiek, werkt op zowel effector- als regulerende T-cellen, verandert de antigenpresenterende celfunctie en induceert de uitscheiding van cytokinen en oplosbare

mediatoren. UVR kan een gunstige biologische impact hebben op de huid, maar is tegelijkertijd ook de belangrijkste milieurisicofactor voor de ontwikkeling van huidkanker. In hoofdstuk 13 worden de moleculaire en cellulaire mechanismen beschreven die momenteel worden erkend om bij te dragen aan foto-carcinogenese. Hoofdstuk 14 gaat in op de bestaande literatuur van vier belangrijke ultraviolette B (UVB) modaliteiten van fototherapie bij de behandeling van psoriasis: heliotherapie, breedband UVB, smalband UVB (NBUVB) en excimerlaser en -lamp. Dit hoofdstuk biedt een geactualiseerd en uitgebreid overzicht van UVB-fototherapieën voor psoriasis om artsen te helpen bij het bepalen van hun keuze van modaliteit en doseringsregime om optimale resultaten voor psoriasispatiënten te verzekeren. Fototherapie was ook de eerste beschikbare behandeling voor vitiligo omdat het de veiligste, efficiëntste en meest gebruikte therapie is. NBUVB is in staat repigmentatie te stimuleren en ziekteregressie te induceren. Deel IV beschrijft de nieuwste technologieën die in dit proefschrift worden gebruikt, zoals massacytometrie en “high-throughput sequencing” van de T-celreceptor (TCR). Hoofdstuk 15 bespreekt de uitdaging van effectieve communicatie tussen wetenschappers en artsen. Tevens vindt introductie plaats van de volgende paar hoofdstukken waarin onderzoekstechnieken in eenvoudige bewoordingen worden beschreven ―“research techniques made simple (RTMS)”. Manuscripten in RTMS format zijn fundamentele hulpmiddelen om onderzoekskennis en vocabulaire te delen die noodzakelijk zijn voor een effectieve communicatie tussen clinici en onderzoekers. Hoofdstuk 16 beschrijft de belangrijkste experimentele methoden voor “mass cytometry by time of flight (CyTOF)” ―een massacytometrie techniek waarbij cellen (gelabeld met een grote serie antilichamen die elk geconjugeerd zijn met een uniek metaalisotoop) geïoniseerd worden, waarna een massaspectrometer de tijd determineert die de verschillende ionen nodig heeft om de detectieplaat te bereiken. Geavanceerde CyTOF kan een grote impact hebben op onze wetenschappelijke kennis. Het succes van massacytometrie-experimenten hangt echter af van het volledig begrijpen van de methode en van het beheersen van variaties bij het maken van vergelijkingen tussen monsters. De uitdaging van het onderzoeken, visualiseren en presenteren van massacytometrie-gegevens heeft de voortdurende ontwikkeling van methoden voor dimensiereductie gemotiveerd. Hoofdstuk 17 bespreekt enkele veelgebruikte en toegankelijke massacytometrie data-analysetools, waaronder Principal Component Analysis (PCA), Spanning-tree Progression Analysis van Density-normalized Events (SPADE), t-distributed stochastic neighbor embedding (t-SNE)-gebaseerde visualisatie (viSNE), automatische classificatie van cellulaire expressie door niet-lineaire stochastische inbedding (ACCENSE) en clusteridentificatie, karakterisering en regressie (CITRUS). High-throughput-sequencing (HTS) van de TCR is een andere nieuwe snel voortschrijdende immunologische techniek die gevoelige en nauwkeurige identificatie en kwantificering mogelijk maakt van elke afzonderlijke T-celkloon die aanwezig is in elk

393

In Deel II is de rol van TRM-cellen in diverse huidziekten bestudeerd, bijvoorbeeld bij psoriasis, graft-versus-host-ziekte (GvHD) en vitiligo. In hoofdstuk 7 is de bijdrage van residente T-celpopulaties bij psoriasis onderzocht. Het toont IL-17 producerende αβ T-celklonen met psoriasisspecifieke antigeenreceptoren die aanwezig zijn in klinisch genezen psoriatische huidlaesies. Mogelijk vertegenwoordigen deze oligoklonale T-celpopulaties een groep van ziekte-initiërende pathogene T-cellen bij psoriasis en zou langdurige beheersing van deze ziekte onderdrukking van deze residente T-cel populaties vereisen. Hoofdstuk 8 analyseert de rol van interleukine-9 (IL-9) als een vroege ontstekingsversterker en de invloed ervan op TRM cellen. IL-9 producerende CD4+ T-helpercellen zijn even frequent aanwezig als IL-17 producerende T-helpercellen (TH17 cellen) bij psoriasis, maar het meeste IL-9 werd geproduceerd door niet-TH17 cellen. IL-9 liet vroege effecten op TRM zien om de pathogene cytokineproductie te verbeteren, hetgeen consistent is met een rol voor IL-9 als een vroege ontstekingsversterker in diverse ontstekingsaandoeningen. In hoofdstuk 9 is de rol van TRM-cellen in GvHD onderzocht. GvHD is een belangrijke oorzaak van ziekte en overlijden bij patiënten na hematopoietische stamceltransplantatie. We laten zien dat wanneer TRM-cellen in de huid worden geprikkeld door allogene donorafgeleide antigenpresenterende cellen, TRM-cellen gaan prolifereren en cytokinen produceren waarvan bekend is dat ze deelnemen aan de pathogenese van GvHD. De resultaten suggereren dat TRM-uitputtingsstrategieën nuttig zouden kunnen zijn bij het verminderen van GvHD. Hoofdstuk 10 onderzoekt hoe cutane TRM-cellen bijdragen aan vitiligo en melanoom, evenals hun potentieel als therapeutische doelen in beide ziekten. De aanwezigheid van autoreactieve TRM-cellen in vitiligo laesies en in muismodellen van vitiligo geven aan dat het richten op deze cellen effectief kan zijn als een duurzame behandelingsstrategie voor vitiligo. Omgekeerd is de inductie van melanoom-reactieve TRM-cellen nodig om effectieve bescherming tegen tumorgroei te bereiken. Deel III beschrijft de waarde van fototherapie voor TRM gerelateerde ziekten, zoals psoriasis en vitiligo. Hoofdstuk 11 introduceert fototherapie als misschien wel de oudste vorm van behandeling in de dermatologie, en die wordt toegepast voor het verbeteren van een breed scala aan huidziekten. Het blijft een uiterst effectieve, veilige en algemeen gebruikte vorm van behandeling. De ultraviolette straling (UVR), afkomstig van de zon of kunstmatige lichtbronnen, heeft een krachtig immunomodulerend effect. Hoofdstuk 12 geeft een overzicht van de immunologische mechanismen waarmee ultraviolette straling verantwoordelijk is voor de therapeutische effecten van fototherapie. UVR activeert meestal het aangeboren immuunsysteem, terwijl het adaptieve immuunsysteem wordt onderdrukt, en leidt tot zowel lokale als systemische effecten. Het effect is antigenspecifiek, werkt op zowel effector- als regulerende T-cellen, verandert de antigenpresenterende celfunctie en induceert de uitscheiding van cytokinen en oplosbare

mediatoren. UVR kan een gunstige biologische impact hebben op de huid, maar is tegelijkertijd ook de belangrijkste milieurisicofactor voor de ontwikkeling van huidkanker. In hoofdstuk 13 worden de moleculaire en cellulaire mechanismen beschreven die momenteel worden erkend om bij te dragen aan foto-carcinogenese. Hoofdstuk 14 gaat in op de bestaande literatuur van vier belangrijke ultraviolette B (UVB) modaliteiten van fototherapie bij de behandeling van psoriasis: heliotherapie, breedband UVB, smalband UVB (NBUVB) en excimerlaser en -lamp. Dit hoofdstuk biedt een geactualiseerd en uitgebreid overzicht van UVB-fototherapieën voor psoriasis om artsen te helpen bij het bepalen van hun keuze van modaliteit en doseringsregime om optimale resultaten voor psoriasispatiënten te verzekeren. Fototherapie was ook de eerste beschikbare behandeling voor vitiligo omdat het de veiligste, efficiëntste en meest gebruikte therapie is. NBUVB is in staat repigmentatie te stimuleren en ziekteregressie te induceren. Deel IV beschrijft de nieuwste technologieën die in dit proefschrift worden gebruikt, zoals massacytometrie en “high-throughput sequencing” van de T-celreceptor (TCR). Hoofdstuk 15 bespreekt de uitdaging van effectieve communicatie tussen wetenschappers en artsen. Tevens vindt introductie plaats van de volgende paar hoofdstukken waarin onderzoekstechnieken in eenvoudige bewoordingen worden beschreven ―“research techniques made simple (RTMS)”. Manuscripten in RTMS format zijn fundamentele hulpmiddelen om onderzoekskennis en vocabulaire te delen die noodzakelijk zijn voor een effectieve communicatie tussen clinici en onderzoekers. Hoofdstuk 16 beschrijft de belangrijkste experimentele methoden voor “mass cytometry by time of flight (CyTOF)” ―een massacytometrie techniek waarbij cellen (gelabeld met een grote serie antilichamen die elk geconjugeerd zijn met een uniek metaalisotoop) geïoniseerd worden, waarna een massaspectrometer de tijd determineert die de verschillende ionen nodig heeft om de detectieplaat te bereiken. Geavanceerde CyTOF kan een grote impact hebben op onze wetenschappelijke kennis. Het succes van massacytometrie-experimenten hangt echter af van het volledig begrijpen van de methode en van het beheersen van variaties bij het maken van vergelijkingen tussen monsters. De uitdaging van het onderzoeken, visualiseren en presenteren van massacytometrie-gegevens heeft de voortdurende ontwikkeling van methoden voor dimensiereductie gemotiveerd. Hoofdstuk 17 bespreekt enkele veelgebruikte en toegankelijke massacytometrie data-analysetools, waaronder Principal Component Analysis (PCA), Spanning-tree Progression Analysis van Density-normalized Events (SPADE), t-distributed stochastic neighbor embedding (t-SNE)-gebaseerde visualisatie (viSNE), automatische classificatie van cellulaire expressie door niet-lineaire stochastische inbedding (ACCENSE) en clusteridentificatie, karakterisering en regressie (CITRUS). High-throughput-sequencing (HTS) van de TCR is een andere nieuwe snel voortschrijdende immunologische techniek die gevoelige en nauwkeurige identificatie en kwantificering mogelijk maakt van elke afzonderlijke T-celkloon die aanwezig is in elk

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biologisch monster. Hoofdstuk 18 gaat in op de methodologie, vooruitgang en beperkingen van HTS van de TCR en beschrijft nieuwe toepassingen van deze techniek op het gebied van dermatologisch onderzoek. We recapituleren de hoofdstukken van deel IV door middel van een quiz in hoofdstuk 19. Het benadrukt de kracht van de RTMS-manuscripten, die niet alleen het manuscript omvatten, maar ook puntsgewijs de voors en tegens benadrukken, voorbeelden van hoe de techniek te gebruiken is, een quiz en een PowerPoint-presentatie waarmee lezers de technieken direct kunnen delen en leren (online beschikbaar als aanvullend materiaal). Ter afsluiting van het proefschrift worden in hoofdstuk 20 de belangrijkste resultaten en definitieve conclusie van deze thesis besproken. Hoofdstuk 21 presenteert de toekomstige perspectieven van TRM cellen in de preventieve en therapeutische geneeskunde.

biologisch monster. Hoofdstuk 18 gaat in op de methodologie, vooruitgang en beperkingen van HTS van de TCR en beschrijft nieuwe toepassingen van deze techniek op het gebied van dermatologisch onderzoek. We recapituleren de hoofdstukken van deel IV door middel van een quiz in hoofdstuk 19. Het benadrukt de kracht van de RTMS-manuscripten, die niet alleen het manuscript omvatten, maar ook puntsgewijs de voors en tegens benadrukken, voorbeelden van hoe de techniek te gebruiken is, een quiz en een PowerPoint-presentatie waarmee lezers de technieken direct kunnen delen en leren (online beschikbaar als aanvullend materiaal). Ter afsluiting van het proefschrift worden in hoofdstuk 20 de belangrijkste resultaten en definitieve conclusie van deze thesis besproken. Hoofdstuk 21 presenteert de toekomstige perspectieven van TRM cellen in de preventieve en therapeutische geneeskunde.

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ABBREVIATIONS

5-HT Serotonin 6-4 PPs 6-4 photoproducts 8-MOP 8-methoxypsoralen 8-oxoG 7,8-dihydro-8-oxoguanosine α-MSH α-melanocyte stimulating hormone A Adenine ACCENSE Automatic Classification of Cellular Expression by Non-linear Stochastic

Embedding ACD Allergic contact dermatitis ADCC Antibody dependent cellular cytotoxicity ALL Acute, lymphocytic leukemia AML Acute myelogenous leukemia ANA Anti-nuclear antibody ANOVA Analysis of variance Anti-TPO Anti-thyroid peroxidase APC Antigen-presenting cell ATG Anti-thymocyte globulin BBUVB Broadband UVB BCC Basal cell carcinoma BER Base excision repair BM Bone Marrow BSA Body surface area bu Busulfan C Cytosine CBC Complete blood count CCR CC chemokine receptors CD Cluster of differentiation CDR3 Complementarity determining region 3 CITRUS Cluster Identification, Characterization, and Regression CGRP Calcitonin gene-related peptide CHS Contact hypersensitivity CLA Cutaneous lymphocyte antigen CLL Chronic lymphocytic leukemia CMML Chronic myelomonocytic leukemia cont Control COX-2 Cyclooxygenase 2 CPDs Cyclobutane pyrimidine dimers CTCL Cutaneous T-cell lymphoma CTLA Cytotoxic T-lymphocyte-associated protein CXCR C-X-C chemokine receptor Cy Cyclophosphamide CyTOF Mass cytometry by time of flight D Diversity DAB 3,3'-diaminobenzidine tetrahydrochloride DAPI 4′,6-diamidino-2-phenylindole DC Dendritic cell DEJ Dermoepidermal junction DEWs Dewar valence isomers DLBCL Diffuse large B cell lymphoma DNA Deoxyribonucleic acid cDNA Complementary DNA EAE Experimental autoimmune encephalomyelitis

eATP Extracellular adenosine triphosphate EDTA Ethylenediaminetetraacetic acid ELAM Endothelial leucocyte adhesion molecule FACS Fluorescence-activated cell sorting FCS Fluorescent cell standard FDE Fixed drug eruptions FFPE Formalin-fixed, paraffin-embedded fib Fibroblasts FISH Fluorescence in situ hybridization FL Follicular lymphoma Flu Fludarabine FoxP3 Forkhead box P3 G Guanine GSH Glutathione GVHD Graft-versus-host disease GZMA Granzyme A GZMB Granzyme B H2O2 Hydrogen peroxide H&E Hematoxylin and eosin HCV Hepatitis C virus HL Hodgkin’s lymphoma HS Human skin HSV Herpes simplex virus HTS High-throughput sequencing ICAM-1 Intercellular adhesion molecule-1 IF Immunofluorescence IFN-γ Interferon-γ IG Immunoglobulin IGg Immunoglobulin G IL Interleukin ILC(s) Innate lymphoid cell(s) Ir Iridium IRF-3 IFN regulatory factor-3 IV Intravenous J Joining JID Journal of Investigative Dermatology Ker Keratinocytes KLRG1 Killer cell lectin-like receptor subfamily G member 1 LAM-PCR Linear amplification–mediated PCR LC(s) Langerhans cell(s) MACS Magnetic-activated cell sorting MAPK Mitogen-activated protein kinase MCA Metal-conjugated antibody MCB Mass-tag cellular barcoding MDA Malondialdehyde MDS Myelodysplastic syndrome MED Minimal erythema doses MF Mycosis fungoides MHC Major histocompatibility complex miRNA MicroRNA MMUR Mismatch unrelated MR Matched related MSH Melanocyte stimulating hormone MST Minimum-spanning tree MTX Methotrexate

397

ABBREVIATIONS

5-HT Serotonin 6-4 PPs 6-4 photoproducts 8-MOP 8-methoxypsoralen 8-oxoG 7,8-dihydro-8-oxoguanosine α-MSH α-melanocyte stimulating hormone A Adenine ACCENSE Automatic Classification of Cellular Expression by Non-linear Stochastic

Embedding ACD Allergic contact dermatitis ADCC Antibody dependent cellular cytotoxicity ALL Acute, lymphocytic leukemia AML Acute myelogenous leukemia ANA Anti-nuclear antibody ANOVA Analysis of variance Anti-TPO Anti-thyroid peroxidase APC Antigen-presenting cell ATG Anti-thymocyte globulin BBUVB Broadband UVB BCC Basal cell carcinoma BER Base excision repair BM Bone Marrow BSA Body surface area bu Busulfan C Cytosine CBC Complete blood count CCR CC chemokine receptors CD Cluster of differentiation CDR3 Complementarity determining region 3 CITRUS Cluster Identification, Characterization, and Regression CGRP Calcitonin gene-related peptide CHS Contact hypersensitivity CLA Cutaneous lymphocyte antigen CLL Chronic lymphocytic leukemia CMML Chronic myelomonocytic leukemia cont Control COX-2 Cyclooxygenase 2 CPDs Cyclobutane pyrimidine dimers CTCL Cutaneous T-cell lymphoma CTLA Cytotoxic T-lymphocyte-associated protein CXCR C-X-C chemokine receptor Cy Cyclophosphamide CyTOF Mass cytometry by time of flight D Diversity DAB 3,3'-diaminobenzidine tetrahydrochloride DAPI 4′,6-diamidino-2-phenylindole DC Dendritic cell DEJ Dermoepidermal junction DEWs Dewar valence isomers DLBCL Diffuse large B cell lymphoma DNA Deoxyribonucleic acid cDNA Complementary DNA EAE Experimental autoimmune encephalomyelitis

eATP Extracellular adenosine triphosphate EDTA Ethylenediaminetetraacetic acid ELAM Endothelial leucocyte adhesion molecule FACS Fluorescence-activated cell sorting FCS Fluorescent cell standard FDE Fixed drug eruptions FFPE Formalin-fixed, paraffin-embedded fib Fibroblasts FISH Fluorescence in situ hybridization FL Follicular lymphoma Flu Fludarabine FoxP3 Forkhead box P3 G Guanine GSH Glutathione GVHD Graft-versus-host disease GZMA Granzyme A GZMB Granzyme B H2O2 Hydrogen peroxide H&E Hematoxylin and eosin HCV Hepatitis C virus HL Hodgkin’s lymphoma HS Human skin HSV Herpes simplex virus HTS High-throughput sequencing ICAM-1 Intercellular adhesion molecule-1 IF Immunofluorescence IFN-γ Interferon-γ IG Immunoglobulin IGg Immunoglobulin G IL Interleukin ILC(s) Innate lymphoid cell(s) Ir Iridium IRF-3 IFN regulatory factor-3 IV Intravenous J Joining JID Journal of Investigative Dermatology Ker Keratinocytes KLRG1 Killer cell lectin-like receptor subfamily G member 1 LAM-PCR Linear amplification–mediated PCR LC(s) Langerhans cell(s) MACS Magnetic-activated cell sorting MAPK Mitogen-activated protein kinase MCA Metal-conjugated antibody MCB Mass-tag cellular barcoding MDA Malondialdehyde MDS Myelodysplastic syndrome MED Minimal erythema doses MF Mycosis fungoides MHC Major histocompatibility complex miRNA MicroRNA MMUR Mismatch unrelated MR Matched related MSH Melanocyte stimulating hormone MST Minimum-spanning tree MTX Methotrexate

398

MUR Matched unrelated MyD88 Myeloid differentiation factor 88 NAD(P)H Nicotinamide adenine dinucleotide (phosphate) NBUVB Narrowband UVB NER Nucleotide excision repair NF-κB Nuclear factor-κB NIAMS National Institute of Arthritis and Musculoskeletal and Skin Diseases NIH National Institute of Health NK Natural killer cell NKT Natural killer T cell NMSC Non-melanoma skin cancer nrLAM-PCR Nonrestrictive LAM-PCR NS Normal skin ns Not significant NSG Non-obese diabetic (NOD) scid gamma OCT Optimal cutting temperature OGG1 8-oxoguanine DNA glycosylase-1 OMP Oral mini pulse Os Osmium PAF Platelet-activating factor PASI Psoriasis Area Severity Index PB Peripheral blood PBMCs Peripheral blood mononuclear cells PBS Phosphate-buffered saline PCA Principal Component Analysis PCR Polymerase chain reaction Pd Palladium PDT Photodynamic therapy PGA Physician Global Assessment PGE2 Prostaglandin E2 PMA Phorbol 12-myristate 13-acetate PPD Tuberculin-purified protein derivative PRF1 Perforin Pt Platinum PTCH Patched PUVA Psoralens and ultraviolet A RACE Rapid Amplification of cDNA Ends RANK Receptor activator of nuclear factor κ B Rh Rhodium RNS Reactive nitrogen species ROS Reactive oxygen species RPMI Roswell Park Memorial Institute RT Room temperature RTMS Research techniques made simple Ru Ruthenium S1P1 Sphingosine-1-phosphate receptor 1 SCC Squamous cell carcinoma SCID Severe combined immunodeficiency SEM Standard error of the mean SFM Serum-free medium Siro Sirolimus snRNA Small nuclear RNA SPADE Spanning-tree Progression Analysis of Density-normalized Events SPF Sun protection factor STR Short tandem repeat

T Thymine Tac Tacrolimus TBI Total body irradiation TBST Tris-buffered saline plus Tween-20 Tc Cytotoxic T cell TCM Central memory T cell TCR T-cell receptor Teff Effector T cell TEM Effector memory T cell TGF-β Transforming growth factor-β Th Helper T cell TLR Toll-like receptors TMM Migratory memory T cell TNF-α Tumor necrosis factor-α Treg Regulatory T cell Treo Treosulfan TRIF Toll-like receptor adaptor molecule 1 TRM Resident memory T cell Tslec Short-lived effector T cell t-SNE T-distributed stochastic neighbor embedding tx Transplant TWEAK TNF related weak inducer of apoptosis V Variable VCAV Vaccinated with vaccinia virus VASI Vitiligo area and severity index VCAM Vascular cell adhesion molecule VETF Vitiligo European task Force VIDA Vitiligo disease activity viSNE T-distributed stochastic neighbor embedding-based visualization vs Versus UCA Urocanic acid untx Untreated mice UVA Ultraviolet A UVB Ultraviolet B UV(R) Ultraviolet (radiation) WHO-EORTC World Health Organization–European Organization for Research and

Treatment of Cancer XP Xeroderma pigmentosum XPA Xeroderma pigmentosum complementation group A

399

MUR Matched unrelated MyD88 Myeloid differentiation factor 88 NAD(P)H Nicotinamide adenine dinucleotide (phosphate) NBUVB Narrowband UVB NER Nucleotide excision repair NF-κB Nuclear factor-κB NIAMS National Institute of Arthritis and Musculoskeletal and Skin Diseases NIH National Institute of Health NK Natural killer cell NKT Natural killer T cell NMSC Non-melanoma skin cancer nrLAM-PCR Nonrestrictive LAM-PCR NS Normal skin ns Not significant NSG Non-obese diabetic (NOD) scid gamma OCT Optimal cutting temperature OGG1 8-oxoguanine DNA glycosylase-1 OMP Oral mini pulse Os Osmium PAF Platelet-activating factor PASI Psoriasis Area Severity Index PB Peripheral blood PBMCs Peripheral blood mononuclear cells PBS Phosphate-buffered saline PCA Principal Component Analysis PCR Polymerase chain reaction Pd Palladium PDT Photodynamic therapy PGA Physician Global Assessment PGE2 Prostaglandin E2 PMA Phorbol 12-myristate 13-acetate PPD Tuberculin-purified protein derivative PRF1 Perforin Pt Platinum PTCH Patched PUVA Psoralens and ultraviolet A RACE Rapid Amplification of cDNA Ends RANK Receptor activator of nuclear factor κ B Rh Rhodium RNS Reactive nitrogen species ROS Reactive oxygen species RPMI Roswell Park Memorial Institute RT Room temperature RTMS Research techniques made simple Ru Ruthenium S1P1 Sphingosine-1-phosphate receptor 1 SCC Squamous cell carcinoma SCID Severe combined immunodeficiency SEM Standard error of the mean SFM Serum-free medium Siro Sirolimus snRNA Small nuclear RNA SPADE Spanning-tree Progression Analysis of Density-normalized Events SPF Sun protection factor STR Short tandem repeat

T Thymine Tac Tacrolimus TBI Total body irradiation TBST Tris-buffered saline plus Tween-20 Tc Cytotoxic T cell TCM Central memory T cell TCR T-cell receptor Teff Effector T cell TEM Effector memory T cell TGF-β Transforming growth factor-β Th Helper T cell TLR Toll-like receptors TMM Migratory memory T cell TNF-α Tumor necrosis factor-α Treg Regulatory T cell Treo Treosulfan TRIF Toll-like receptor adaptor molecule 1 TRM Resident memory T cell Tslec Short-lived effector T cell t-SNE T-distributed stochastic neighbor embedding tx Transplant TWEAK TNF related weak inducer of apoptosis V Variable VCAV Vaccinated with vaccinia virus VASI Vitiligo area and severity index VCAM Vascular cell adhesion molecule VETF Vitiligo European task Force VIDA Vitiligo disease activity viSNE T-distributed stochastic neighbor embedding-based visualization vs Versus UCA Urocanic acid untx Untreated mice UVA Ultraviolet A UVB Ultraviolet B UV(R) Ultraviolet (radiation) WHO-EORTC World Health Organization–European Organization for Research and

Treatment of Cancer XP Xeroderma pigmentosum XPA Xeroderma pigmentosum complementation group A

LIST OF CONTRIBUTING AUTHORS Ahmed Gehad Department of Dermatology, Brigham and Women’s Hospital, Harvard Medical School, Boston, USA. Anders T. Aasebø Department of Pathology, University of Oslo and Oslo University Hospital - Rikshospitalet, Oslo, Norway. Beatrice Dyring-Andersen Department of Dermatology, Brigham and Women’s Hospital, Harvard Medical School, Boston, USA. Bram van den Broek BioImaging Facility, The Netherlands Cancer Institute, Amsterdam, The Netherlands.

Chao Yang Department of Dermatology, Brigham and Women’s Hospital, Harvard Medical School, Boston, USA. Christoph Schlapbach Department of Dermatology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland. Christopher Elco Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, USA. Corey S. Cutler Division of Hematological Malignancies and Stem Cell Transplantation, Dana-Farber Cancer Institute, Boston, USA. Cornelia L. Trimble Department of Gynecology and Obstetrics, Johns Hopkins Medical Institutions, Baltimore, USA. David W Vredevoogd Division of Molecular Oncology & Immunology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands.

David Hamm Adaptive Biotechnologies, Seattle, USA.

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LIST OF CONTRIBUTING AUTHORS Ahmed Gehad Department of Dermatology, Brigham and Women’s Hospital, Harvard Medical School, Boston, USA. Anders T. Aasebø Department of Pathology, University of Oslo and Oslo University Hospital - Rikshospitalet, Oslo, Norway. Beatrice Dyring-Andersen Department of Dermatology, Brigham and Women’s Hospital, Harvard Medical School, Boston, USA. Bram van den Broek BioImaging Facility, The Netherlands Cancer Institute, Amsterdam, The Netherlands.

Chao Yang Department of Dermatology, Brigham and Women’s Hospital, Harvard Medical School, Boston, USA. Christoph Schlapbach Department of Dermatology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland. Christopher Elco Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, USA. Corey S. Cutler Division of Hematological Malignancies and Stem Cell Transplantation, Dana-Farber Cancer Institute, Boston, USA. Cornelia L. Trimble Department of Gynecology and Obstetrics, Johns Hopkins Medical Institutions, Baltimore, USA. David W Vredevoogd Division of Molecular Oncology & Immunology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands.

David Hamm Adaptive Biotechnologies, Seattle, USA.

402

Edgar L. Milford Renal Transplant Program, Division of Renal Medicine, Brigham and Women’s Hospital, Boston, USA. Elizabeth L. Lowry Department of Dermatology, Brigham and Women’s Hospital, Harvard Medical School, Boston, USA. Espen S. Bækkevold Department of Pathology, University of Oslo and Oslo University Hospital - Rikshospitalet, Oslo, Norway. Feline E Dijkgraaf Division of Molecular Oncology & Immunology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands. Frode L. Jahnsen Department of Pathology, University of Oslo and Oslo University Hospital - Rikshospitalet, Oslo, Norway. Geraldine S. Pinkus Department of Hematology, Institute of Clinical Medicine, University of Oslo and Oslo University Hospital - Rikshospitalet, Oslo, Norway. Haesook T. Kim Biostatistics and Computational Biology,Dana-Farber Cancer Institute,Boston,USA. Harlan S. Robins Adaptive Biotechnologies, Seattle, USA. Henrik Reims Department of Pathology, Oslo University Hospital - Rikshospitalet, Oslo, Norway. Hongye Liu

Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, USA. Harvard Medical School, Boston, USA.

Ilan R. Kirsch Adaptive Biotechnologies, Seattle, USA. Indira Guleria Renal Transplant Program, Division of Renal Medicine, Brigham and Women’s Hospital, Boston, USA. James G. Krueger Department of Dermatology, Rockefeller University, New York, NY, USA.

Jerome Ritz Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, USA. Harvard Medical School, Boston, USA. Jessica E. Teague Department of Dermatology, Brigham and Women’s Hospital, Harvard Medical School, Boston, USA. Ji-Ying Song Animal Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands. John T. O’Malley

Department of Dermatology, Brigham and Women’s Hospital, Harvard Medical School, Boston, USA. John W. Liang Department of Dermatology, Brigham and Women’s Hospital, Boston, USA. Joost B Beltman Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands. Jude Hilaire Department of Hematology, Institute of Clinical Medicine, University of Oslo and Oslo University Hospital - Rikshospitalet, Oslo, Norway. Laura Campbell Department of Dermatology, Brigham and Women’s Hospital, Harvard Medical School, Boston, USA. Marcel BM Teunissen Department of Dermatology and Netherlands Institute for Pigment Disorders, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands. Marcella Willemsen Department of Dermatology and Netherlands Institute for Pigment Disorders, Amsterdam University Medical Centers, University of Amsterdam, Cancer Center Amsterdam, Amsterdam Infection & Immunity Institute, Amsterdam, The Netherlands. Margarida Apetato Department of Dermatology and Venereology, Centro Hospitalar de Lisboa Central, Lisbon, Portugal. Margarida Moura Valejo Coelho Department of Dermatology and Venereology, Centro Hospitalar de Lisboa Central, Lisbon, Portugal.

403

Edgar L. Milford Renal Transplant Program, Division of Renal Medicine, Brigham and Women’s Hospital, Boston, USA. Elizabeth L. Lowry Department of Dermatology, Brigham and Women’s Hospital, Harvard Medical School, Boston, USA. Espen S. Bækkevold Department of Pathology, University of Oslo and Oslo University Hospital - Rikshospitalet, Oslo, Norway. Feline E Dijkgraaf Division of Molecular Oncology & Immunology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands. Frode L. Jahnsen Department of Pathology, University of Oslo and Oslo University Hospital - Rikshospitalet, Oslo, Norway. Geraldine S. Pinkus Department of Hematology, Institute of Clinical Medicine, University of Oslo and Oslo University Hospital - Rikshospitalet, Oslo, Norway. Haesook T. Kim Biostatistics and Computational Biology,Dana-Farber Cancer Institute,Boston,USA. Harlan S. Robins Adaptive Biotechnologies, Seattle, USA. Henrik Reims Department of Pathology, Oslo University Hospital - Rikshospitalet, Oslo, Norway. Hongye Liu

Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, USA. Harvard Medical School, Boston, USA.

Ilan R. Kirsch Adaptive Biotechnologies, Seattle, USA. Indira Guleria Renal Transplant Program, Division of Renal Medicine, Brigham and Women’s Hospital, Boston, USA. James G. Krueger Department of Dermatology, Rockefeller University, New York, NY, USA.

Jerome Ritz Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, USA. Harvard Medical School, Boston, USA. Jessica E. Teague Department of Dermatology, Brigham and Women’s Hospital, Harvard Medical School, Boston, USA. Ji-Ying Song Animal Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands. John T. O’Malley

Department of Dermatology, Brigham and Women’s Hospital, Harvard Medical School, Boston, USA. John W. Liang Department of Dermatology, Brigham and Women’s Hospital, Boston, USA. Joost B Beltman Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands. Jude Hilaire Department of Hematology, Institute of Clinical Medicine, University of Oslo and Oslo University Hospital - Rikshospitalet, Oslo, Norway. Laura Campbell Department of Dermatology, Brigham and Women’s Hospital, Harvard Medical School, Boston, USA. Marcel BM Teunissen Department of Dermatology and Netherlands Institute for Pigment Disorders, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands. Marcella Willemsen Department of Dermatology and Netherlands Institute for Pigment Disorders, Amsterdam University Medical Centers, University of Amsterdam, Cancer Center Amsterdam, Amsterdam Infection & Immunity Institute, Amsterdam, The Netherlands. Margarida Apetato Department of Dermatology and Venereology, Centro Hospitalar de Lisboa Central, Lisbon, Portugal. Margarida Moura Valejo Coelho Department of Dermatology and Venereology, Centro Hospitalar de Lisboa Central, Lisbon, Portugal.

404

Marjolijn Mertz BioImaging Facility, The Netherlands Cancer Institute, Amsterdam, The Netherlands.

Mark Hoogenboezem Research Facility, Sanquin, Amsterdam, The Netherlands. Martin C. Mihm Department of Dermatology, Brigham and Women’s Hospital, Boston, USA. Menno A. de Rie Academic Medical Center, Department of Dermatology, University of Amsterdam, Amsterdam, The Netherlands. Michael Hagerstrom Department of Hematology, Institute of Clinical Medicine, University of Oslo and Oslo University Hospital - Rikshospitalet, Oslo, Norway. Mireille Toebes

Division of Molecular Oncology & Immunology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands. Mitra Dowlatshahi Department of Dermatology, Brigham and Women’s Hospital, Harvard Medical School, Boston, USA.

Pei-Chen Department of Dermatology, Brigham and Women’s Hospital, Boston, USA. Rachael A. Clark Department of Dermatology, Brigham and Women’s Hospital, Harvard Medical School, Boston, USA. Robert J. Soiffer Division of Hematological Malignancies and Stem Cell Transplantation, Dana-Farber Cancer Institute, Boston, USA. Rosalie M Luiten Department of Dermatology and Netherlands Institute for Pigment Disorders, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands.

Rugile Linkutė Department of Dermatology and Netherlands Institute for Pigment Disorders, Amsterdam University Medical Centers, University of Amsterdam, Cancer Center Amsterdam, Amsterdam Infection & Immunity Institute, Amsterdam, The Netherlands. Sherrie J. Divito Department of Dermatology, Brigham and Women’s Hospital, Boston, USA.

Thomas S. Kupper Department of Dermatology, Brigham and Women’s Hospital, Harvard Medical School, Boston, USA. Tobias Gedde-Dahl Department of Hematology, Institute of Clinical Medicine, University of Oslo and Oslo University Hospital - Rikshospitalet, Oslo, Norway. Ton N Schumacher

Division of Molecular Oncology & Immunology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands. Tsui C. Ling Consultant Dermatologist for Phototherapy and Photobiology Unit, Dermatology Centre, Salford Royal Hospital, Manchester, UK. Vaneeta Sheth Department of Dermatology; Brigham and Women’s Hospital, Harvard Medical School, Boston, USA. Newton-Wellesley Hospital, Newton, USA. Vincent T. Ho Division of Hematological Malignancies and Stem Cell Transplantation, Dana-Farber Cancer Institute, Boston, USA. Victor Huang Department of Dermatology, Brigham and Women’s Hospital, Harvard Medical School, Boston, USA.

405

Marjolijn Mertz BioImaging Facility, The Netherlands Cancer Institute, Amsterdam, The Netherlands.

Mark Hoogenboezem Research Facility, Sanquin, Amsterdam, The Netherlands. Martin C. Mihm Department of Dermatology, Brigham and Women’s Hospital, Boston, USA. Menno A. de Rie Academic Medical Center, Department of Dermatology, University of Amsterdam, Amsterdam, The Netherlands. Michael Hagerstrom Department of Hematology, Institute of Clinical Medicine, University of Oslo and Oslo University Hospital - Rikshospitalet, Oslo, Norway. Mireille Toebes

Division of Molecular Oncology & Immunology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands. Mitra Dowlatshahi Department of Dermatology, Brigham and Women’s Hospital, Harvard Medical School, Boston, USA.

Pei-Chen Department of Dermatology, Brigham and Women’s Hospital, Boston, USA. Rachael A. Clark Department of Dermatology, Brigham and Women’s Hospital, Harvard Medical School, Boston, USA. Robert J. Soiffer Division of Hematological Malignancies and Stem Cell Transplantation, Dana-Farber Cancer Institute, Boston, USA. Rosalie M Luiten Department of Dermatology and Netherlands Institute for Pigment Disorders, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands.

Rugile Linkutė Department of Dermatology and Netherlands Institute for Pigment Disorders, Amsterdam University Medical Centers, University of Amsterdam, Cancer Center Amsterdam, Amsterdam Infection & Immunity Institute, Amsterdam, The Netherlands. Sherrie J. Divito Department of Dermatology, Brigham and Women’s Hospital, Boston, USA.

Thomas S. Kupper Department of Dermatology, Brigham and Women’s Hospital, Harvard Medical School, Boston, USA. Tobias Gedde-Dahl Department of Hematology, Institute of Clinical Medicine, University of Oslo and Oslo University Hospital - Rikshospitalet, Oslo, Norway. Ton N Schumacher

Division of Molecular Oncology & Immunology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands. Tsui C. Ling Consultant Dermatologist for Phototherapy and Photobiology Unit, Dermatology Centre, Salford Royal Hospital, Manchester, UK. Vaneeta Sheth Department of Dermatology; Brigham and Women’s Hospital, Harvard Medical School, Boston, USA. Newton-Wellesley Hospital, Newton, USA. Vincent T. Ho Division of Hematological Malignancies and Stem Cell Transplantation, Dana-Farber Cancer Institute, Boston, USA. Victor Huang Department of Dermatology, Brigham and Women’s Hospital, Harvard Medical School, Boston, USA.

LIST OF PUBLICATIONS Publications included in this thesis Dijkgraaf FE, Matos TR, Hoogenboezem M, Toebes M, Vredevoogd DW, Mertz M, van den Broek B, Song JY, Teunissen MBM, Luiten RM, Beltman JB, Schumacher TN. Tissue patrol by resident memory CD8+ T cells in human skin. Nat Immunol. 2019 May 20 Willemsen M, Linkute R, Luiten RM, Matos TR. Skin-resident memory T cells as a potential new therapeutic target in vitiligo and melanoma. Pigment Cell Melanoma Res. 2019. In Press. Gehad A, Teague JE, Matos TR, Huang V, Yang C, Watanabe R, O'Malley JT, Trimble CL, Kupper TS, Clark RA. A primary role for human central memory cells in tissue immunosurveillance. Blood Adv. 2018 Feb 13;2(3):292-298. Matos TR, O’Malley JT, Lowry EL, Hamm D, Kirsch IR, Robins HS, Kupper TS, Krueger JG, Clark RA. Disease-specific IL-17-producing α T-cell clones in clinically resolved psoriasis. J Clin Invest. 2017 Nov 1;127(11):4031-4041. Matos TR. The Challenge of Effective Communication among Scientists. J Invest Dermatol. 2017 Nov;137(11):e183-e184. Matos TR, de Rie MA, Teunissen MB. RTMS: High-Throughput Sequencing of the T-Cell Receptor. J Invest Dermatol. 2017 Jun;137(6):e131ee138. Matos TR, Hongye L, Ritz J. RTMS: Mass Cytometry Analysis Tools for Decrypting the Complexity of Biological Systems. J Invest Dermatol. 2017 May;137(5):e43–e51. Matos TR, Hongye L, Ritz J. RTMS: Experimental Methodology for Single-Cell Mass Cytometry. J Invest Dermatol. 2017 Apr;137(4):e31-e38. Matos TR, de Rie MA. Discovery of skin lymphocytes was a game changer in experimental dermatology. Exp Dermatol. 2017 Aug;26(8):683-684. Matos TR, Sheth V. The symbiosis of phototherapy and photoimmunology. Clin Dermatol. 2016 Sep-Oct;34(5):538-47. Matos TR, Ling TC, Sheth V. Ultraviolet B radiation therapy for psoriasis: Pursuing the optimal regime. Clin Dermatol. 2016 Sep-Oct;34(5):587-93 Matos TR, Sheth V. Novel applications of Phototherapy. Clin Dermatol. 2016 Sep-Oct;34(5):529-31. Coelho MMV, Matos TR, Apetato M. The dark side of the light: mechanisms of photocarcinogenesis. Clin Dermatol. 2016 Sep-Oct;34(5):563-70.

407

LIST OF PUBLICATIONS Publications included in this thesis Dijkgraaf FE, Matos TR, Hoogenboezem M, Toebes M, Vredevoogd DW, Mertz M, van den Broek B, Song JY, Teunissen MBM, Luiten RM, Beltman JB, Schumacher TN. Tissue patrol by resident memory CD8+ T cells in human skin. Nat Immunol. 2019 May 20 Willemsen M, Linkute R, Luiten RM, Matos TR. Skin-resident memory T cells as a potential new therapeutic target in vitiligo and melanoma. Pigment Cell Melanoma Res. 2019. In Press. Gehad A, Teague JE, Matos TR, Huang V, Yang C, Watanabe R, O'Malley JT, Trimble CL, Kupper TS, Clark RA. A primary role for human central memory cells in tissue immunosurveillance. Blood Adv. 2018 Feb 13;2(3):292-298. Matos TR, O’Malley JT, Lowry EL, Hamm D, Kirsch IR, Robins HS, Kupper TS, Krueger JG, Clark RA. Disease-specific IL-17-producing α T-cell clones in clinically resolved psoriasis. J Clin Invest. 2017 Nov 1;127(11):4031-4041. Matos TR. The Challenge of Effective Communication among Scientists. J Invest Dermatol. 2017 Nov;137(11):e183-e184. Matos TR, de Rie MA, Teunissen MB. RTMS: High-Throughput Sequencing of the T-Cell Receptor. J Invest Dermatol. 2017 Jun;137(6):e131ee138. Matos TR, Hongye L, Ritz J. RTMS: Mass Cytometry Analysis Tools for Decrypting the Complexity of Biological Systems. J Invest Dermatol. 2017 May;137(5):e43–e51. Matos TR, Hongye L, Ritz J. RTMS: Experimental Methodology for Single-Cell Mass Cytometry. J Invest Dermatol. 2017 Apr;137(4):e31-e38. Matos TR, de Rie MA. Discovery of skin lymphocytes was a game changer in experimental dermatology. Exp Dermatol. 2017 Aug;26(8):683-684. Matos TR, Sheth V. The symbiosis of phototherapy and photoimmunology. Clin Dermatol. 2016 Sep-Oct;34(5):538-47. Matos TR, Ling TC, Sheth V. Ultraviolet B radiation therapy for psoriasis: Pursuing the optimal regime. Clin Dermatol. 2016 Sep-Oct;34(5):587-93 Matos TR, Sheth V. Novel applications of Phototherapy. Clin Dermatol. 2016 Sep-Oct;34(5):529-31. Coelho MMV, Matos TR, Apetato M. The dark side of the light: mechanisms of photocarcinogenesis. Clin Dermatol. 2016 Sep-Oct;34(5):563-70.

408

Watanabe R, Gehad A, Yang C, Campbell L, Teague JE, Schlapbach C, Elco C, Huang V, Matos TR, Kupper TS, Clark RA. Human skin is protected by four functionally and phenotypically discrete populations of resident and recirculating memory T cells. Sci Trans Med, 2015 Mar 18;7(279):279ra39 Other publications Groth C*, van Groningen LFJ*, Matos TR, Bremmers ME, Preijers FWMB, Dolstra H, Reicherts C, Schaap NPM, van Hooren EHG, IntHout J, Masereeuw R, Netea MG, Levine JE, Morales G, Ferrara JL, Blijlevens NMA, van Oosterhout YVJM, Stelljes M, van der Velden WJFM. Phase I/II Trial of a Combination of Anti-CD3/CD7 Immunotoxins for Steroid-Refractory Acute Graft-versus-Host Disease. Biol Blood Marrow Transplant. 2019 Apr;25(4):712-719. *Both authors contributed equally Hirakawa M, Matos T, Liu H, Koreth J, Kim HT, Paul N, Murase K, Whangbo J, Alho AC, Nikiforow S, Cutler C, Ho VT, Armand P, Alyea EP, Antin JH, Blazar BR, Lacerda JF, Soiffer RJ, Ritz J. Low-dose interleukine-2 selectively activates discrete subsets of CD4 regulatory T cells and natural killer cells. JCI Insight. 2016 Nov 3;1(18):e89278. Koolen PG, Matos TR, Ibrahim AM, Sun J, Lee BT, Frankenthaler RA, Lin SJ. Recurrence Rates Over 20 Years in the Treatment of Malignant Melanoma: Immediate Versus Delayed Reconstruction. Plast Reconstr Surg Glob Open. 2017 Jul 12;5(7):e1378. Lampson BL, Kasar SK, Matos TR, Morgan EA, Rassenti L, Davids MS, Fisher DC, Freedman AS, Jacobson CA, Armand P, Abramson JS, Arnason JE, Kipps TJ, Fein J, Fernandes S, Hanna J, Ritz J, Kim HT, Brown JR. Idelalisib Given Front-line for Treatment of Chronic Lymphocytic Leukemia Causes Frequent Immune-Mediated Hepatotoxicity. Blood. 2016. 128(2), 195-203. Alho AC, Kim HT, Chammas MJ, Reynolds CG, Matos TR, Forcade E, Whangbo J, Nikiforow S, Cutler CS, Koreth J, Ho VT, Armand P, Antin JH, Alyea EP, Lacerda JF, Soiffer RJ, Ritz J. Unbalanced recovery of regulatory and effector T cells after allogeneic stem cell transplantation contributes to chronic GVHD. Blood. 2016 4;127(5):646-57.

Watanabe R, Gehad A, Yang C, Campbell L, Teague JE, Schlapbach C, Elco C, Huang V, Matos TR, Kupper TS, Clark RA. Human skin is protected by four functionally and phenotypically discrete populations of resident and recirculating memory T cells. Sci Trans Med, 2015 Mar 18;7(279):279ra39 Other publications Groth C*, van Groningen LFJ*, Matos TR, Bremmers ME, Preijers FWMB, Dolstra H, Reicherts C, Schaap NPM, van Hooren EHG, IntHout J, Masereeuw R, Netea MG, Levine JE, Morales G, Ferrara JL, Blijlevens NMA, van Oosterhout YVJM, Stelljes M, van der Velden WJFM. Phase I/II Trial of a Combination of Anti-CD3/CD7 Immunotoxins for Steroid-Refractory Acute Graft-versus-Host Disease. Biol Blood Marrow Transplant. 2019 Apr;25(4):712-719. *Both authors contributed equally Hirakawa M, Matos T, Liu H, Koreth J, Kim HT, Paul N, Murase K, Whangbo J, Alho AC, Nikiforow S, Cutler C, Ho VT, Armand P, Alyea EP, Antin JH, Blazar BR, Lacerda JF, Soiffer RJ, Ritz J. Low-dose interleukine-2 selectively activates discrete subsets of CD4 regulatory T cells and natural killer cells. JCI Insight. 2016 Nov 3;1(18):e89278. Koolen PG, Matos TR, Ibrahim AM, Sun J, Lee BT, Frankenthaler RA, Lin SJ. Recurrence Rates Over 20 Years in the Treatment of Malignant Melanoma: Immediate Versus Delayed Reconstruction. Plast Reconstr Surg Glob Open. 2017 Jul 12;5(7):e1378. Lampson BL, Kasar SK, Matos TR, Morgan EA, Rassenti L, Davids MS, Fisher DC, Freedman AS, Jacobson CA, Armand P, Abramson JS, Arnason JE, Kipps TJ, Fein J, Fernandes S, Hanna J, Ritz J, Kim HT, Brown JR. Idelalisib Given Front-line for Treatment of Chronic Lymphocytic Leukemia Causes Frequent Immune-Mediated Hepatotoxicity. Blood. 2016. 128(2), 195-203. Alho AC, Kim HT, Chammas MJ, Reynolds CG, Matos TR, Forcade E, Whangbo J, Nikiforow S, Cutler CS, Koreth J, Ho VT, Armand P, Antin JH, Alyea EP, Lacerda JF, Soiffer RJ, Ritz J. Unbalanced recovery of regulatory and effector T cells after allogeneic stem cell transplantation contributes to chronic GVHD. Blood. 2016 4;127(5):646-57.

Name PhD student: Tiago R. Matos

PhD period: June 2016 to November 2019

Name PhD supervisor: Prof. dr. M.A. de Rie & Prof. dr. R.A. Clark

1. PhD training Year Workload

(Hours/ECTS)

Courses

- Entrepreneurship in Health and Life Sciences. ACE, IXA, AMC & VUmc.

2019

1.5

- Management and leadership development programme, ESDR.

2019 2

- Project Management, AMC. 2019 1.5

- Active learner, AMC. 2019 2

- Coach the Co, AMC. 2019 2

- Teaching skills for Ph.D. candidates. UvA. 2019 0.5

- Elementary course regulation and organization for clinical Researchers (BROK®), NFU BROK Academie.

2017 1.0

- Fundamentals of Immunology: Death by Friendly Fire, Rice University through edX.

2017 1.6

- Advanced Immunology Course, VUmc Academy. 2017 2.9

- AMC World of Science, AMC. 2016 0.7

- Citation Analysis and Impact Factors, AMC. 2016 0.4

Language courses - Cursus Spreken en Schrijven voor Gevorderden,

University of Amsterdam (UvA)

2018

4

- Hoe met patienten te praten – Workshop AMC 2017 0.3

- Intensieve Nederlands taaltraining – Language Institute Regina Coeli

2017 1.6

- Netherlands taalcursus – TopTaal; Staatsexamen NT2 II voltooid

2016- 2017 14

411

Name PhD student: Tiago R. Matos

PhD period: June 2016 to November 2019

Name PhD supervisor: Prof. dr. M.A. de Rie & Prof. dr. R.A. Clark

1. PhD training Year Workload

(Hours/ECTS)

Courses

- Entrepreneurship in Health and Life Sciences. ACE, IXA, AMC & VUmc.

2019

1.5

- Management and leadership development programme, ESDR.

2019 2

- Project Management, AMC. 2019 1.5

- Active learner, AMC. 2019 2

- Coach the Co, AMC. 2019 2

- Teaching skills for Ph.D. candidates. UvA. 2019 0.5

- Elementary course regulation and organization for clinical Researchers (BROK®), NFU BROK Academie.

2017 1.0

- Fundamentals of Immunology: Death by Friendly Fire, Rice University through edX.

2017 1.6

- Advanced Immunology Course, VUmc Academy. 2017 2.9

- AMC World of Science, AMC. 2016 0.7

- Citation Analysis and Impact Factors, AMC. 2016 0.4

Language courses - Cursus Spreken en Schrijven voor Gevorderden,

University of Amsterdam (UvA)

2018

4

- Hoe met patienten te praten – Workshop AMC 2017 0.3

- Intensieve Nederlands taaltraining – Language Institute Regina Coeli

2017 1.6

- Netherlands taalcursus – TopTaal; Staatsexamen NT2 II voltooid

2016- 2017 14

412

Oral conference presentations

- EADV Guest Lecture - Skin resident T cells: Implications for immune homeostasis and disease. (Keynote speaker - Plenary session) ESDR Conference, France.

2019

1.0

- A phase I/II study on the anti-CD3/CD7 immunotoxin combination for the treatment of steroid-refractory acute GVHD. ESDR Conference, France.

2019 1.0

- Human central memory T cells generate superior numbers of resident memory T cells in skin. Nederlandse Vereniging voor Experimentele Dermatologie, the Netherlands

2019 0.5

- Human central memory T cells generate superior numbers of resident memory T cells in skin (Plenary session). International Investigative Dermatology Congress, USA

2018 1.0

- Mass Cytometry Identifies T-Cell Populations Associated with Severe Hepatotoxicity in CLL Patients on Upfront Idelalisib. American Society of Haematology Congress, USA

2018 1.0

- Skin-resident T cells: Implications for cutaneous immune homeostasis (Plenary session) – Investigation Day; University of Lisbon. Portugal

2018 0.5

- A phase I/II study on the anti-CD3/CD7 immunotoxin combination (T-Guard) for the treatment of steroid-refractory acute GVHD. American Society of Haematology Congress, USA

2017 1.0

- The pathogenic T cells in Psoriasis. Academy of Future leaders in Dermatology – European Society of Dermatological Research, Spain

2017 1.5

- Identifying the pathogenic T cells in Psoriasis. The Amsterdam Infection & Immunity (AI&II) Institute Retreat, the Netherlands

2017 0.5

- Identifying the pathogenic T cells in Psoriasis. – Investigation Day; University of Lisbon. Portugal

2016 0.5

- Recipient skin resident memory T cells can induce GvHD-like dermatitis in human engrafted mice. Society of Investigative Dermatology Congress, USA.

2016 1.0

- Multiple human memory T cell subsets can give rise to resident memory T cells in skin. Society of Investigative Dermatology Congress, USA

2016 1.0

Poster conference presentations

- The putative role of skin resident memory T cells in acute Graft-versus-Host-Disease. Nederlandse Vereniging voor Experimentele Dermatologie, the Netherlands.

2017

0.5

Conferences & Meetings

- European Society of Dermatological Research Congress. France

2019

1.2

- The Next Web Congress, the Netherlands 2019 1.0

- DIO (Dermatologen In Opleiding) dagen, the Netherlands

2019 0.4

- Nederlandse Vereniging voor Experimentele Dermatologie Meeting, the Netherlands

2019 0.5

- International Investigative Dermatology Congress, USA 2018 1.2

- DIO (Dermatologen In Opleiding) dagen, the Netherlands

2018 0.4

- Investigation Day Meeting; University of Lisbon. Portugal

2018 0.5

- The Amsterdam Infection & Immunity (AI&II) Institute Retreat, the Netherlands

2017 0.5

- Nederlandse Vereniging voor Experimentele Dermatologie Meeting, the Netherlands

2017 1.0

- Society of Investigative Dermatology Congress, USA. 2016 1.0

413

Oral conference presentations

- EADV Guest Lecture - Skin resident T cells: Implications for immune homeostasis and disease. (Keynote speaker - Plenary session) ESDR Conference, France.

2019

1.0

- A phase I/II study on the anti-CD3/CD7 immunotoxin combination for the treatment of steroid-refractory acute GVHD. ESDR Conference, France.

2019 1.0

- Human central memory T cells generate superior numbers of resident memory T cells in skin. Nederlandse Vereniging voor Experimentele Dermatologie, the Netherlands

2019 0.5

- Human central memory T cells generate superior numbers of resident memory T cells in skin (Plenary session). International Investigative Dermatology Congress, USA

2018 1.0

- Mass Cytometry Identifies T-Cell Populations Associated with Severe Hepatotoxicity in CLL Patients on Upfront Idelalisib. American Society of Haematology Congress, USA

2018 1.0

- Skin-resident T cells: Implications for cutaneous immune homeostasis (Plenary session) – Investigation Day; University of Lisbon. Portugal

2018 0.5

- A phase I/II study on the anti-CD3/CD7 immunotoxin combination (T-Guard) for the treatment of steroid-refractory acute GVHD. American Society of Haematology Congress, USA

2017 1.0

- The pathogenic T cells in Psoriasis. Academy of Future leaders in Dermatology – European Society of Dermatological Research, Spain

2017 1.5

- Identifying the pathogenic T cells in Psoriasis. The Amsterdam Infection & Immunity (AI&II) Institute Retreat, the Netherlands

2017 0.5

- Identifying the pathogenic T cells in Psoriasis. – Investigation Day; University of Lisbon. Portugal

2016 0.5

- Recipient skin resident memory T cells can induce GvHD-like dermatitis in human engrafted mice. Society of Investigative Dermatology Congress, USA.

2016 1.0

- Multiple human memory T cell subsets can give rise to resident memory T cells in skin. Society of Investigative Dermatology Congress, USA

2016 1.0

Poster conference presentations

- The putative role of skin resident memory T cells in acute Graft-versus-Host-Disease. Nederlandse Vereniging voor Experimentele Dermatologie, the Netherlands.

2017

0.5

Conferences & Meetings

- European Society of Dermatological Research Congress. France

2019

1.2

- The Next Web Congress, the Netherlands 2019 1.0

- DIO (Dermatologen In Opleiding) dagen, the Netherlands

2019 0.4

- Nederlandse Vereniging voor Experimentele Dermatologie Meeting, the Netherlands

2019 0.5

- International Investigative Dermatology Congress, USA 2018 1.2

- DIO (Dermatologen In Opleiding) dagen, the Netherlands

2018 0.4

- Investigation Day Meeting; University of Lisbon. Portugal

2018 0.5

- The Amsterdam Infection & Immunity (AI&II) Institute Retreat, the Netherlands

2017 0.5

- Nederlandse Vereniging voor Experimentele Dermatologie Meeting, the Netherlands

2017 1.0

- Society of Investigative Dermatology Congress, USA. 2016 1.0

414

2. Teaching

Year Workload (Hours/ECTS)

Lecturing

- Invited lecturer for the course of Translational Sciences of the Infection and Immunity – Master’s Program from the University of Amsterdam

• “Skin resident T cells - key players in cutaneous immune homeostasis”

• “Experimental models to study the human immune system”

• “Hematopoietic stem cell transplantation”

2017, 2018, 2019

2017, 2018, 2019

2017

8.0

Tutoring, Mentoring, Supervision

- Olivier Schiphorst, Research Elective Student, Universiteit van Amsterdam

2018 & 2019

3.0

- Siebe Blok, Research Elective Student, Vrije Universiteit Amsterdam

2018 & 2019 3.0

- Lars Neleman, Research Elective Student, UMCG 2018 3.0

- Marcella Willemsen, PhD candidate (Informal) 2016-2019 7.0

Other

- Thesis examiner of student Rosie Sikkel, University of Amsterdam

2017

0.3

3. Parameters of Esteem

Year

Grants

- Lilly Scholarship

- René Touraine Foundation

- Young Investigator Award from Adaptive Biotechnologies

- EADV Research Fellowship

- Amsterdam Infection & Immunity Institute Travel Grant

- National Psoriasis Foundation Research Fellowship

2019

2016

2017

2018

2018

2016-2016

Awards & Honours

- 1st Prize Entrepreneurship in Health and Life Sciences. ACE, IXA, AMC & VUmc.

2019

- Nominated for Academy for Future Leaders in Dermatology (Management and leadership development programme), ESDR.

2019

- EADV Keynote Guest Lecturer. ESDR Conference. 2019

- Nominated for International Resident Retreat at the IID. SID, ESDR, JSID.

2018

- IID Travel Award 2018

- Nominated for Academy of Future Leaders in Dermatology by ESDR. 2017

- Best oral presentation. Retreat AI&II. 2017

- Featured at the Meet the Investigator Series of Journal of Investigative Dermatology.

2017

- Best Presentation. 18th Annual NVED Scientific Meeting, Netherlands.

2017

- ESDR/SID Collegiality Award, USA. 2016

415

2. Teaching

Year Workload (Hours/ECTS)

Lecturing

- Invited lecturer for the course of Translational Sciences of the Infection and Immunity – Master’s Program from the University of Amsterdam

• “Skin resident T cells - key players in cutaneous immune homeostasis”

• “Experimental models to study the human immune system”

• “Hematopoietic stem cell transplantation”

2017, 2018, 2019

2017, 2018, 2019

2017

8.0

Tutoring, Mentoring, Supervision

- Olivier Schiphorst, Research Elective Student, Universiteit van Amsterdam

2018 & 2019

3.0

- Siebe Blok, Research Elective Student, Vrije Universiteit Amsterdam

2018 & 2019 3.0

- Lars Neleman, Research Elective Student, UMCG 2018 3.0

- Marcella Willemsen, PhD candidate (Informal) 2016-2019 7.0

Other

- Thesis examiner of student Rosie Sikkel, University of Amsterdam

2017

0.3

3. Parameters of Esteem

Year

Grants

- Lilly Scholarship

- René Touraine Foundation

- Young Investigator Award from Adaptive Biotechnologies

- EADV Research Fellowship

- Amsterdam Infection & Immunity Institute Travel Grant

- National Psoriasis Foundation Research Fellowship

2019

2016

2017

2018

2018

2016-2016

Awards & Honours

- 1st Prize Entrepreneurship in Health and Life Sciences. ACE, IXA, AMC & VUmc.

2019

- Nominated for Academy for Future Leaders in Dermatology (Management and leadership development programme), ESDR.

2019

- EADV Keynote Guest Lecturer. ESDR Conference. 2019

- Nominated for International Resident Retreat at the IID. SID, ESDR, JSID.

2018

- IID Travel Award 2018

- Nominated for Academy of Future Leaders in Dermatology by ESDR. 2017

- Best oral presentation. Retreat AI&II. 2017

- Featured at the Meet the Investigator Series of Journal of Investigative Dermatology.

2017

- Best Presentation. 18th Annual NVED Scientific Meeting, Netherlands.

2017

- ESDR/SID Collegiality Award, USA. 2016

416

4. Publications

Year

Peer reviewed

- Willemsen M, Linkute R, Luiten RM, Matos TR. Skin-resident memory T cells as a potential new therapeutic target in vitiligo and melanoma. Pigment Cell Melanoma Res. 2019.

2019

- Dijkgraaf FE, Matos TR, Hoogenboezem M, Toebes M, Vredevoogd DW, Mertz M, van den Broek B, Song JY, Teunissen MBM, Luiten RM, Beltman JB, Schumacher TN. Tissue patrol by resident memory CD8+ T cells in human skin. Nat Immunol. 2019 May 20

2019

- Groth C, van Groningen LFJ, Matos TR, Bremmers ME, Preijers FWMB, Dolstra H, Reicherts C, Schaap NPM, van Hooren EHG, IntHout J, Masereeuw R, Netea MG, Levine JE, Morales G, Ferrara JL, Blijlevens NMA, van Oosterhout YVJM, Stelljes M, van der Velden WJFM. Phase I/II Trial of a Combination of Anti-CD3/CD7 Immunotoxins for Steroid-Refractory Acute Graft-versus-Host Disease. Biol Blood Marrow Transplant. 2019 Apr;25(4):712-719

2019

- Gehad A, Teague JE, Matos TR, Huang V, Yang C, Watanabe R, O'Malley JT, Trimble CL, Kupper TS, Clark RA. A primary role for human central memory cells in tissue immunosurveillance. Blood Adv. 2018 Feb 13;2(3):292-298

2018

- Matos TR, O’Malley JT, Lowry EL, Hamm D, Kirsch IR, Robins HS, Kupper TS, Krueger JG, Clark RA. Disease-specific IL-17-producing α T-cell clones in clinically resolved psoriasis. J Clin Invest. 2017 Nov 1;127(11):4031-4041

2017

- Matos TR. The Challenge of Effective Communication among Scientists. J Invest Dermatol. 2017 Nov;137(11):e183-e184

2017

- Matos TR, de Rie MA, Teunissen MB. RTMS: High-Throughput Sequencing of the T-Cell Receptor. J Invest Dermatol. 2017 Jun;137(6):e131ee138

2017

- Matos TR, Hongye L, Ritz J. RTMS: Mass Cytometry Analysis Tools for Decrypting the Complexity of Biological Systems. J Invest Dermatol. 2017 May;137(5):e43–e51

2017

- Matos TR, Hongye L, Ritz J. RTMS: Experimental Methodology for Single-Cell Mass Cytometry. J Invest Dermatol. 2017 Apr;137(4): e31-e38

2017

- Matos TR, de Rie MA. Discovery of skin lymphocytes was a game changer in experimental dermatology. Exp Dermatol. 2017 Aug;26(8):683-684

2017

- Koolen PG, Matos TR, Ibrahim AM, Sun J, Lee BT, Frankenthaler RA, Lin SJ. Recurrence Rates Over 20 Years in the Treatment of Malignant Melanoma: Immediate Versus Delayed Reconstruction. Plast Reconstr Surg Glob Open. 2017 Jul 12;5(7):e1378

2017

- Hirakawa M, Matos TR, Liu H, Koreth J, Kim HT, Paul N, Murase K, Whangbo J, Alho AC, Nikiforow S, Cutler C, Ho VT, Armand P, Alyea EP, Antin JH, Blazar BR, Lacerda JF, Soiffer RJ, Ritz J. Low-dose interleukine-2 selectively activates discrete subsets of CD4 regulatory T cells and natural killer cells. JCI Insight. 2016 Nov 3;1(18):e89278

2016

- Matos TR, Sheth V. The symbiosis of phototherapy and photoimmunology. Clin Dermatol. 2016. 2016 Sep-Oct;34(5):538-47

2016

- Matos TR, Ling TC, Sheth V. Ultraviolet B radiation therapy for psoriasis: Pursuing the optimal regime. Clin Dermatol. 2016 Sep-Oct;34(5):587-93

2016

- Matos TR, Sheth V. Novel applications of Phototherapy. Clin Dermatol. 2016 Sep-Oct;34(5):529-31

2016

- Coelho MMV, Matos TR, Apetato M. The dark side of the light: mechanisms of photocarcinogenesis. Clin Dermatol. 2016 Sep-Oct;34(5):563-70

2016

- Lampson BL, Kasar SK, Matos TR, Morgan EA, Rassenti L, Davids MS, Fisher DC, Freedman AS, Jacobson CA, Armand P, Abramson JS, Arnason JE, Kipps TJ, Fein J, Fernandes S, Hanna J, Ritz J, Kim HT, Brown JR. Idelalisib Given Front-line for Treatment of Chronic Lymphocytic Leukemia Causes Frequent Immune-Mediated Hepatotoxicity. Blood. 2016. 128(2), 195-203

2016

- Alho AC, Kim HT, Chammas MJ, Reynolds CG, Matos TR, Forcade E, Whangbo J, Nikiforow S, Cutler CS, Koreth J, Ho VT, Armand P, Antin JH, Alyea EP, Lacerda JF, Soiffer RJ, Ritz J. Unbalanced recovery of regulatory and effector T cells after allogeneic stem cell transplantation contributes to chronic GVHD. Blood. 2016 4;127(5):646-57

2016

- Watanabe R, Gehad A, Yang C, Campbell L, Teague JE, Schlapbach C, Elco C, Huang V, Matos TR, Kupper TS, Clark RA. Human skin is protected by four functionally and phenotypically discrete populations of resident and recirculating memory T cells. Sci Trans Med, 2015 Mar 18;7(279):279ra39

2015

417

4. Publications

Year

Peer reviewed

- Willemsen M, Linkute R, Luiten RM, Matos TR. Skin-resident memory T cells as a potential new therapeutic target in vitiligo and melanoma. Pigment Cell Melanoma Res. 2019.

2019

- Dijkgraaf FE, Matos TR, Hoogenboezem M, Toebes M, Vredevoogd DW, Mertz M, van den Broek B, Song JY, Teunissen MBM, Luiten RM, Beltman JB, Schumacher TN. Tissue patrol by resident memory CD8+ T cells in human skin. Nat Immunol. 2019 May 20

2019

- Groth C, van Groningen LFJ, Matos TR, Bremmers ME, Preijers FWMB, Dolstra H, Reicherts C, Schaap NPM, van Hooren EHG, IntHout J, Masereeuw R, Netea MG, Levine JE, Morales G, Ferrara JL, Blijlevens NMA, van Oosterhout YVJM, Stelljes M, van der Velden WJFM. Phase I/II Trial of a Combination of Anti-CD3/CD7 Immunotoxins for Steroid-Refractory Acute Graft-versus-Host Disease. Biol Blood Marrow Transplant. 2019 Apr;25(4):712-719

2019

- Gehad A, Teague JE, Matos TR, Huang V, Yang C, Watanabe R, O'Malley JT, Trimble CL, Kupper TS, Clark RA. A primary role for human central memory cells in tissue immunosurveillance. Blood Adv. 2018 Feb 13;2(3):292-298

2018

- Matos TR, O’Malley JT, Lowry EL, Hamm D, Kirsch IR, Robins HS, Kupper TS, Krueger JG, Clark RA. Disease-specific IL-17-producing α T-cell clones in clinically resolved psoriasis. J Clin Invest. 2017 Nov 1;127(11):4031-4041

2017

- Matos TR. The Challenge of Effective Communication among Scientists. J Invest Dermatol. 2017 Nov;137(11):e183-e184

2017

- Matos TR, de Rie MA, Teunissen MB. RTMS: High-Throughput Sequencing of the T-Cell Receptor. J Invest Dermatol. 2017 Jun;137(6):e131ee138

2017

- Matos TR, Hongye L, Ritz J. RTMS: Mass Cytometry Analysis Tools for Decrypting the Complexity of Biological Systems. J Invest Dermatol. 2017 May;137(5):e43–e51

2017

- Matos TR, Hongye L, Ritz J. RTMS: Experimental Methodology for Single-Cell Mass Cytometry. J Invest Dermatol. 2017 Apr;137(4): e31-e38

2017

- Matos TR, de Rie MA. Discovery of skin lymphocytes was a game changer in experimental dermatology. Exp Dermatol. 2017 Aug;26(8):683-684

2017

- Koolen PG, Matos TR, Ibrahim AM, Sun J, Lee BT, Frankenthaler RA, Lin SJ. Recurrence Rates Over 20 Years in the Treatment of Malignant Melanoma: Immediate Versus Delayed Reconstruction. Plast Reconstr Surg Glob Open. 2017 Jul 12;5(7):e1378

2017

- Hirakawa M, Matos TR, Liu H, Koreth J, Kim HT, Paul N, Murase K, Whangbo J, Alho AC, Nikiforow S, Cutler C, Ho VT, Armand P, Alyea EP, Antin JH, Blazar BR, Lacerda JF, Soiffer RJ, Ritz J. Low-dose interleukine-2 selectively activates discrete subsets of CD4 regulatory T cells and natural killer cells. JCI Insight. 2016 Nov 3;1(18):e89278

2016

- Matos TR, Sheth V. The symbiosis of phototherapy and photoimmunology. Clin Dermatol. 2016. 2016 Sep-Oct;34(5):538-47

2016

- Matos TR, Ling TC, Sheth V. Ultraviolet B radiation therapy for psoriasis: Pursuing the optimal regime. Clin Dermatol. 2016 Sep-Oct;34(5):587-93

2016

- Matos TR, Sheth V. Novel applications of Phototherapy. Clin Dermatol. 2016 Sep-Oct;34(5):529-31

2016

- Coelho MMV, Matos TR, Apetato M. The dark side of the light: mechanisms of photocarcinogenesis. Clin Dermatol. 2016 Sep-Oct;34(5):563-70

2016

- Lampson BL, Kasar SK, Matos TR, Morgan EA, Rassenti L, Davids MS, Fisher DC, Freedman AS, Jacobson CA, Armand P, Abramson JS, Arnason JE, Kipps TJ, Fein J, Fernandes S, Hanna J, Ritz J, Kim HT, Brown JR. Idelalisib Given Front-line for Treatment of Chronic Lymphocytic Leukemia Causes Frequent Immune-Mediated Hepatotoxicity. Blood. 2016. 128(2), 195-203

2016

- Alho AC, Kim HT, Chammas MJ, Reynolds CG, Matos TR, Forcade E, Whangbo J, Nikiforow S, Cutler CS, Koreth J, Ho VT, Armand P, Antin JH, Alyea EP, Lacerda JF, Soiffer RJ, Ritz J. Unbalanced recovery of regulatory and effector T cells after allogeneic stem cell transplantation contributes to chronic GVHD. Blood. 2016 4;127(5):646-57

2016

- Watanabe R, Gehad A, Yang C, Campbell L, Teague JE, Schlapbach C, Elco C, Huang V, Matos TR, Kupper TS, Clark RA. Human skin is protected by four functionally and phenotypically discrete populations of resident and recirculating memory T cells. Sci Trans Med, 2015 Mar 18;7(279):279ra39

2015

418

Editorial Activities

Journal of Investigative Dermatology Reviewer

2016 - 2019

British Journal of Dermatology Reviewer 2016 - 2019

Guest Editor of Clinics in Dermatology 2016

CURRICULUM VITAE

Tiago dos Reis Matos was born on June 29th, 1988, in Faro, Portugal. From an early age, Tiago was interested in science, travelling and learning about different cultures and their history. From the age of 12 he was nominated to be part of the European Comenius Program, which enabled him to host students from different European countries (Italy, Bulgaria and Latvia) at his house and school. This also gave him the opportunity to live with host families and attend schools in Sicily (Italy) and Sofia (Bulgaria). In 2007 Tiago graduated from the High School João de Deus with honors. During his high school period, he not only won the 1st prize at a national Biotechnology Contest (taking him to visit the factory and laboratories of Genzyme in Belgium), but he also volunteered for the “Association for Familiar Planning” and the international “MakePovertyHistory Project”, which granted him the Social Performance Prize during 4 consecutive years. Later in 2007, Tiago moved to Lisbon to study medicine at the University of Lisbon. Since his first year, he took part in multiple research internships, receiving numerous scholarships. He gained investigative experience in a wide range of subjects, such as in Rheumatology, Molecular Biology, Neurology, Physiology, Oncology and Dermatology. He has always been very much interested in teaching and helping younger students, which led him to be elected tutor and lecturer of Physiology, Neurophysiology and Cellular & Molecular Biology. Furthermore, Tiago kept on participating in numerous volunteering projects, including “Teddy Bear Hospital”, “Medicina Mais Perto” (promoting health and performing screenings in poor regions) and even participate in health television programs. In 2010 he received an ERASMUS Program Scholarship, allowing him to do his 4th year of medical studies in Prague (Czech Republic) at the First Faculty of Medicine of Charles University. He then received a second ERASMUS Programme Scholarship allowing him to continue his medical studies at the Central Manchester University Hospitals in Manchester (UK). While in Manchester, he also conducted research at the Institute of Brain, Behavior and Mental Health (PI: Prof. Stuart Pickering-Brown) and Institute of Inflammation and Repair (Dermatology, PI: Prof. Dr. Ralf Paus). In 2013, Tiago graduated from his Integrated Master’s Degree in Medicine with honors (MD, MSc). During the same year, he was granted a Harvard Medical School scholarship, which allowed him to move to Boston and

419

Editorial Activities

Journal of Investigative Dermatology Reviewer

2016 - 2019

British Journal of Dermatology Reviewer 2016 - 2019

Guest Editor of Clinics in Dermatology 2016

CURRICULUM VITAE

Tiago dos Reis Matos was born on June 29th, 1988, in Faro, Portugal. From an early age, Tiago was interested in science, travelling and learning about different cultures and their history. From the age of 12 he was nominated to be part of the European Comenius Program, which enabled him to host students from different European countries (Italy, Bulgaria and Latvia) at his house and school. This also gave him the opportunity to live with host families and attend schools in Sicily (Italy) and Sofia (Bulgaria). In 2007 Tiago graduated from the High School João de Deus with honors. During his high school period, he not only won the 1st prize at a national Biotechnology Contest (taking him to visit the factory and laboratories of Genzyme in Belgium), but he also volunteered for the “Association for Familiar Planning” and the international “MakePovertyHistory Project”, which granted him the Social Performance Prize during 4 consecutive years. Later in 2007, Tiago moved to Lisbon to study medicine at the University of Lisbon. Since his first year, he took part in multiple research internships, receiving numerous scholarships. He gained investigative experience in a wide range of subjects, such as in Rheumatology, Molecular Biology, Neurology, Physiology, Oncology and Dermatology. He has always been very much interested in teaching and helping younger students, which led him to be elected tutor and lecturer of Physiology, Neurophysiology and Cellular & Molecular Biology. Furthermore, Tiago kept on participating in numerous volunteering projects, including “Teddy Bear Hospital”, “Medicina Mais Perto” (promoting health and performing screenings in poor regions) and even participate in health television programs. In 2010 he received an ERASMUS Program Scholarship, allowing him to do his 4th year of medical studies in Prague (Czech Republic) at the First Faculty of Medicine of Charles University. He then received a second ERASMUS Programme Scholarship allowing him to continue his medical studies at the Central Manchester University Hospitals in Manchester (UK). While in Manchester, he also conducted research at the Institute of Brain, Behavior and Mental Health (PI: Prof. Stuart Pickering-Brown) and Institute of Inflammation and Repair (Dermatology, PI: Prof. Dr. Ralf Paus). In 2013, Tiago graduated from his Integrated Master’s Degree in Medicine with honors (MD, MSc). During the same year, he was granted a Harvard Medical School scholarship, which allowed him to move to Boston and

420

conduct research at the laboratory of Prof. Dr. Jerome Ritz (Medical Oncology/Hematology at Dana Farber Cancer Institute / Harvard Medical School). Tiago was later invited to continue as a post-doctoral Research Fellow at Prof. Ritz’ laboratory. While in Boston, Tiago worked simultaneously at Prof. Rachael Clark Laboratory (Dermatology, Brigham and Women’s Hospital / Harvard Medical School). In 2016 Tiago moved to Amsterdam (The Netherlands) in order to conclude his PhD thesis. Since 2018, he is working as a medical resident in Dermatology and Venerology (AIOS) at the Amsterdam UMC-University of Amsterdam. Tiago has received numerous grants (Luso-American Foundation, American Skin Association, Astrazeteca-Portugal, Dana-Farber Cancer Institute Medical Oncology Grant program, National Psoriasis Foundation, René Touraine Foundation, European Association of Dermatology & Venerology Research Fellowship), presented his work at various national and international conferences (ASH, SID, ESDR, NVED, IID) and has been nominated to take part in the Roche Continents Program, SID PhD Retreat, IID International Resident Retreat, AI&II Retreat and ESDR Academy of Future Leaders in Dermatology. Furthermore, he has published original articles in prominent journals including Nature Immunology, Journal of Investigative Dermatology, Blood, Science Translational Medicine and Journal of Clinical Investigation.

Currently, Tiago continues to focus on his residency in Dermatology, to conduct research through collaborative projects, to teach and supervise numerous students.

Acknowledgements This thesis was only possible thanks to everyone who in one way or another supported, influenced, guided and challenged me. I have therefore many people to thank, surely more than those here mentioned. I am forever grateful to you all! Dear Prof. dr. R. A. Clark, dear Rachael, there will never be enough words to express how thankful I am to all that you have done for me. When I saw your talk at the IID 2013, my world was shaken. I got such an excitement for science, but especially for T cells. You instantly became my idol; a rock star! I am so extremely lucky for having the chance to work with you. Thank you for dedicating your precious time to help me grow. You thought me how to write grants, papers, make presentations, analyze and present data. You guided me in achieving successful collaborations. You provided me with opportunities to become known among research peers. And when I considered moving to the Netherlands, you gave me strength and support, allowing me to take on a new adventure as a resident in Dermatology. You were not only supportive of my career but also of my personal life. Most of all thank you for believing in me and giving me a voice. You completely changed my future and I will always be your biggest and most loyal fan. I will promote and try to support you in any way I can. I admire so much the genius that you are, the brilliancy and speed of your thoughts and creativity of ideas. Your determination and hard work are truly inspirational. Working with you was what made me the happiest during my time in Boston and it is what I will miss the most. I hope to make you proud as your mentee and I am forever grateful for being part of the team Rachael Clark!! THANK YOU SO SO VERY MUCH! Dear Prof. dr. M. A. de Rie, dear Menno, I am so very grateful to have you as my mentor! We first met during the AAD 2015 in San Francisco. Little did I know, that you would become my boss, but mostly my trusted mentor. Thank you so very much for supporting me all the way; even before I moved to the Netherlands. It has been a very rocky road since the moment I decided to move here… extremely difficult years, full of challenges and many uncertainties. It was no doubt one of the biggest challenges I had to go through. A years-long and continuous test of endurance on living and working in a foreigner culture with a different language. However, it has all been possible thanks to your continuous guidance and support!

421

conduct research at the laboratory of Prof. Dr. Jerome Ritz (Medical Oncology/Hematology at Dana Farber Cancer Institute / Harvard Medical School). Tiago was later invited to continue as a post-doctoral Research Fellow at Prof. Ritz’ laboratory. While in Boston, Tiago worked simultaneously at Prof. Rachael Clark Laboratory (Dermatology, Brigham and Women’s Hospital / Harvard Medical School). In 2016 Tiago moved to Amsterdam (The Netherlands) in order to conclude his PhD thesis. Since 2018, he is working as a medical resident in Dermatology and Venerology (AIOS) at the Amsterdam UMC-University of Amsterdam. Tiago has received numerous grants (Luso-American Foundation, American Skin Association, Astrazeteca-Portugal, Dana-Farber Cancer Institute Medical Oncology Grant program, National Psoriasis Foundation, René Touraine Foundation, European Association of Dermatology & Venerology Research Fellowship), presented his work at various national and international conferences (ASH, SID, ESDR, NVED, IID) and has been nominated to take part in the Roche Continents Program, SID PhD Retreat, IID International Resident Retreat, AI&II Retreat and ESDR Academy of Future Leaders in Dermatology. Furthermore, he has published original articles in prominent journals including Nature Immunology, Journal of Investigative Dermatology, Blood, Science Translational Medicine and Journal of Clinical Investigation.

Currently, Tiago continues to focus on his residency in Dermatology, to conduct research through collaborative projects, to teach and supervise numerous students.

Acknowledgements This thesis was only possible thanks to everyone who in one way or another supported, influenced, guided and challenged me. I have therefore many people to thank, surely more than those here mentioned. I am forever grateful to you all! Dear Prof. dr. R. A. Clark, dear Rachael, there will never be enough words to express how thankful I am to all that you have done for me. When I saw your talk at the IID 2013, my world was shaken. I got such an excitement for science, but especially for T cells. You instantly became my idol; a rock star! I am so extremely lucky for having the chance to work with you. Thank you for dedicating your precious time to help me grow. You thought me how to write grants, papers, make presentations, analyze and present data. You guided me in achieving successful collaborations. You provided me with opportunities to become known among research peers. And when I considered moving to the Netherlands, you gave me strength and support, allowing me to take on a new adventure as a resident in Dermatology. You were not only supportive of my career but also of my personal life. Most of all thank you for believing in me and giving me a voice. You completely changed my future and I will always be your biggest and most loyal fan. I will promote and try to support you in any way I can. I admire so much the genius that you are, the brilliancy and speed of your thoughts and creativity of ideas. Your determination and hard work are truly inspirational. Working with you was what made me the happiest during my time in Boston and it is what I will miss the most. I hope to make you proud as your mentee and I am forever grateful for being part of the team Rachael Clark!! THANK YOU SO SO VERY MUCH! Dear Prof. dr. M. A. de Rie, dear Menno, I am so very grateful to have you as my mentor! We first met during the AAD 2015 in San Francisco. Little did I know, that you would become my boss, but mostly my trusted mentor. Thank you so very much for supporting me all the way; even before I moved to the Netherlands. It has been a very rocky road since the moment I decided to move here… extremely difficult years, full of challenges and many uncertainties. It was no doubt one of the biggest challenges I had to go through. A years-long and continuous test of endurance on living and working in a foreigner culture with a different language. However, it has all been possible thanks to your continuous guidance and support!

422

You have always believed in me, especially when most people doubted. You gave me the freedom, guidance and tools to conduct my own projects and collaborations. You had the patience to help me through my despair when collaborations failed and moderated my excitement on new ambitious ideas or projects. You promote my growth as a scientist, but also mentor and encourage me as a resident in Dermatology & Venereology. Thank you for also being so understanding and supportive with personal matters. My admiration for you keeps on growing. I’m inspired by your multifaceted success as an Immunologist, the leader of an academical-medical department and how you are an active member of so many international associations and thereby are shaping the future of Dermatology! I am immensely grateful! THANK YOU SO SO VERY MUCH! Marcel Teunissen: Thank you very much for all the support and guidance during my time in Amsterdam and to the completion of my Ph.D. I have really enjoyed working with you. Members of the Ph.D. committee, Prof. dr. P.I. Spuls, Prof. dr. H.J.C. de Vries, Prof. dr. R.M. Luiten, Dr. E.H.J. van den Bogaard, Dr. D.J. Hijnen, Prof. dr. M.H. Vermeer, thank you for taking part in my Ph.D. committee and for your critical evaluation of my thesis. Ahmed (The True Magnificent) and Jess (The Glorious), working with you was such a tremendous joy! You are both so extremely sincere and passionate for science. You are both great and passionate scientists, but above all you are some of the nicest people that I had the chance to work with throughout my entire career. Ahmed, I miss laughing with you! You have a great sense of humour, which made me laugh endless times. Jess, your patience and support are endless. You have such a power of reassurance; when working with you, I always felt so serene and knew we would always succeed. More than colleagues, you are my friends, companions. I wish I could work with you all my life! You helped me during some shaken times and you were always happy and available to help in any way possible. I truly miss you and really hope to see you soon. If you ever get the chance to visit the Netherlands, I would love to host and guide you around! Big Big hug! John it was such a privilege to work with you. I was inspired by your determination, intelligence and hard work. I often wondered how you managed to do it all while remaining so serene, and while having a beautiful family! You were always so much fun to work with and the best conference buddy! Can’t wait you see you again or work together! Feline, working with you was always so exciting and fun! Even though the project was extremely ambitious, it was so easy to work with you! You are a wonderful person, hard-

working and incredibly talented scientist! It was in fact an honour working with you and Ton. I am so very thankful for the opportunity! Karina and Gabrielle: I really miss the days we worked together. But I do not miss the cold office! Hehe! Thank you so very much for the “warm” welcome to the lab. You were many times the only support I had. You allowed me to thrive during a very uncertain and difficult period. Thank you for your patience, for teaching me Dutch (including all the Dutch children’s books) and for being more than just colleagues – you were caring friends! I am forever grateful! Saskia thank you for helping at any time, with no hesitation or restrictions! I am so happy every time I see you and always have so much fun with you. You are such a joyful and smart person! Thank you! Marcella, it was so nice working with you, thank you for all your help! You have such a bright future in front of you! Rosalie, thank you very much for welcoming me to your incredible lab and among such a wonderful team of people. Thank you for mentoring me and guiding me in very crucial and complex situations and periods. Thank you for allowing me to grow and become a better researcher. Wouter, Walbert, Nathalie and arts-onderzoekers, it was incredibly nice to work with you! This work would not have been possible without you! Thank you for always being willing to help and being such incredible colleagues. Looking forward to work many more times together!! To all my AIOS colleagues, thank you all for helping me through my journey in becoming a dermatologist in a foreignr country, with a new language (Dutch). Thank you for your support, understanding and patience. I couldn’t have done it without you! You all contributed differently and in small and big personal ways. I am extremely grateful to work with you! THANK YOU VERY MUCH! Yannick, you have been more that a colleague, a true friend. I am extremely lucky to have your continuous support. Thank you very very much for all the help you have been giving me all the way. For teaching me so much, for being a confident and a true friend! For always being there when I needed, make sure I succeeded and finished my Ph.D. while staying in residency. I know I can always count on you and you can always count on me too! Also, a big kiss to the most incredible, funniest and sweet confident Margaux!

423

You have always believed in me, especially when most people doubted. You gave me the freedom, guidance and tools to conduct my own projects and collaborations. You had the patience to help me through my despair when collaborations failed and moderated my excitement on new ambitious ideas or projects. You promote my growth as a scientist, but also mentor and encourage me as a resident in Dermatology & Venereology. Thank you for also being so understanding and supportive with personal matters. My admiration for you keeps on growing. I’m inspired by your multifaceted success as an Immunologist, the leader of an academical-medical department and how you are an active member of so many international associations and thereby are shaping the future of Dermatology! I am immensely grateful! THANK YOU SO SO VERY MUCH! Marcel Teunissen: Thank you very much for all the support and guidance during my time in Amsterdam and to the completion of my Ph.D. I have really enjoyed working with you. Members of the Ph.D. committee, Prof. dr. P.I. Spuls, Prof. dr. H.J.C. de Vries, Prof. dr. R.M. Luiten, Dr. E.H.J. van den Bogaard, Dr. D.J. Hijnen, Prof. dr. M.H. Vermeer, thank you for taking part in my Ph.D. committee and for your critical evaluation of my thesis. Ahmed (The True Magnificent) and Jess (The Glorious), working with you was such a tremendous joy! You are both so extremely sincere and passionate for science. You are both great and passionate scientists, but above all you are some of the nicest people that I had the chance to work with throughout my entire career. Ahmed, I miss laughing with you! You have a great sense of humour, which made me laugh endless times. Jess, your patience and support are endless. You have such a power of reassurance; when working with you, I always felt so serene and knew we would always succeed. More than colleagues, you are my friends, companions. I wish I could work with you all my life! You helped me during some shaken times and you were always happy and available to help in any way possible. I truly miss you and really hope to see you soon. If you ever get the chance to visit the Netherlands, I would love to host and guide you around! Big Big hug! John it was such a privilege to work with you. I was inspired by your determination, intelligence and hard work. I often wondered how you managed to do it all while remaining so serene, and while having a beautiful family! You were always so much fun to work with and the best conference buddy! Can’t wait you see you again or work together! Feline, working with you was always so exciting and fun! Even though the project was extremely ambitious, it was so easy to work with you! You are a wonderful person, hard-

working and incredibly talented scientist! It was in fact an honour working with you and Ton. I am so very thankful for the opportunity! Karina and Gabrielle: I really miss the days we worked together. But I do not miss the cold office! Hehe! Thank you so very much for the “warm” welcome to the lab. You were many times the only support I had. You allowed me to thrive during a very uncertain and difficult period. Thank you for your patience, for teaching me Dutch (including all the Dutch children’s books) and for being more than just colleagues – you were caring friends! I am forever grateful! Saskia thank you for helping at any time, with no hesitation or restrictions! I am so happy every time I see you and always have so much fun with you. You are such a joyful and smart person! Thank you! Marcella, it was so nice working with you, thank you for all your help! You have such a bright future in front of you! Rosalie, thank you very much for welcoming me to your incredible lab and among such a wonderful team of people. Thank you for mentoring me and guiding me in very crucial and complex situations and periods. Thank you for allowing me to grow and become a better researcher. Wouter, Walbert, Nathalie and arts-onderzoekers, it was incredibly nice to work with you! This work would not have been possible without you! Thank you for always being willing to help and being such incredible colleagues. Looking forward to work many more times together!! To all my AIOS colleagues, thank you all for helping me through my journey in becoming a dermatologist in a foreignr country, with a new language (Dutch). Thank you for your support, understanding and patience. I couldn’t have done it without you! You all contributed differently and in small and big personal ways. I am extremely grateful to work with you! THANK YOU VERY MUCH! Yannick, you have been more that a colleague, a true friend. I am extremely lucky to have your continuous support. Thank you very very much for all the help you have been giving me all the way. For teaching me so much, for being a confident and a true friend! For always being there when I needed, make sure I succeeded and finished my Ph.D. while staying in residency. I know I can always count on you and you can always count on me too! Also, a big kiss to the most incredible, funniest and sweet confident Margaux!

424

Dr. Mireille van der Linden, it is such a joy each time I see you! Thank you for saving me in a period when I was so lost trying to survive as a Dutch clinician. You altruistically invested your own time to mentor me and teach me Dutch. You not only thought me Dutch, you made me feel welcome and hopeful. To this day you are an incredible supervisor, giving the best tips on how to communicate with patients! Everyone loves you! And I am no exception! Thank you so very much! I am forever grateful; you have no idea how much it meant to me. Dr. Jan Mekkes, thank you so very much for being the best opleider anyone can ask for. For always defending our interests so rightfully. For your endless patience and for sharing your humongous knowledge with us. For making us laugh with your sense of humor. For not being judgmental and allowing me to openly share my thoughts and concerns. Furthermore, even though I am an outlier, I thank you for never making me feel like one. To all other dermatologists from the Amsterdam UMC, thank you for your training, empathy and patience with this foreigner with a thick (sometimes non-understandable) accent. Thank you for all you have taught me and for supporting me during my Ph.D. To all my GGD colleagues, thank you so very much for the wonderful, fun and inspiring time that I had while working with you at the GGD Amsterdam. I was always so happy to go to work, and it was one of the best working experiences I ever had. I miss it! Thank you for the vote of confidence; my first Dutch job and the opportunity to practice Dutch with the patients. I have so much respect and love for you all! Thank you! Meghan, I was so very lucky to have had the opportunity to join you as a roommate in the beautiful and wonderful apartment at Melrose 31th. I loved every second we lived together. It was in every way perfect! You really made my time in Boston unforgettable! I miss those days very much! I miss you! You will always be in my heart! THANK YOU! My Boston Family, Paulo Branco, Lisa, Fallan, PJ, Mark, Dana, Everly, Luke and Lila, thank you SO VERY much for hosting me without any reservations, even without having met me before. You made sure I felt home, safe and welcomed; from the moment I landed in Boston. Furthermore, you also helped my friends/colleagues. You embraced me into your family and provided me with numerous unforgettable moments. I will forever remember your hugs, our laughs, the delicious food (including the legendary Pig roast) and the many moments we shared together. You are a beautiful and very strong family. I am so proud to be part of it! Love you all! Thank you!

All my incredible friends in Boston – Josephine, Mark, Jan-Willem, Sjors, Hannah, Bote, Klaas, Thomas, Pim, Maaike, Lauren, Lisa, Dominique, Ana, Ines, Joana, Mariana and many others. I will never forget the many adventures and fun we had together. I only wish we would see each other more often. Thank for all your support and for making it an unforgettable experience! Pieter en Wijnand, you made my time in Boston magical! We had so much fun together! From P-town, Upstate New York, Club café, Paradise, snow-ball fights, many diners and even introducing me to Pieter! I am so grateful for all the love and support that you gave me ever since, both in Boston and in Amsterdam! You are extraordinary friends! Thank SO you very very much! Aos meus irmãos do coração, Dany, Flávio e Manuel: Quem diria que após tantos anos estaríamos cada vez mais inseparáveis. Mesmo vivendo em 4 países diferentes, estamos cada vez mais próximos. Vocês sempre me ajudaram, apoiaram, mas acima de tudo dão-me tanta alegria e risos, sem qualquer criticismo. Aconteça o que acontecer sei que me ajudarão sempre no que for preciso (como o têm feito). Adoro-vos muito, e como sempre mal posso esperar para estarmos novamente juntos!!! Muito, muito obrigado meus irmãos!!! Minha adorada família de Santa Maria, Tias, Tios e Primos, desde pequenino que me recebem de braços abertos, me acompanham em tudo e me dão todo o vosso carinho. Obrigado pelos divertidos Natais e férias maravilhosas que sempre me proporcionaram. Amo-vos muito muito! Tia Zina, José, Kenley e Wendy, muito obrigado pelo afeto, supporte e dedicação que me dão continuamente. Sei que posso sempre contar convosco. Amo-vos tanto tanto! Quem me dera que estivessemos mais perto! Minhas lindas avós, Iva e Marta, estou-vos muito grato por tudo o que vocês me ensinaram. Pelo amor que me dão. Sempre a tentar seguir os vossos conselhos, amo-vos muito. Rita, Catarina, Filipa, Cláudia, Iolanda, Daniela, Inês, Micaela e Joana, muitíssimo obrigado pela vossa amizade! Após tantas aventuras conjuntas, vocês são como família! Sem duvida que eu não teria alcançado esta etápa se não fosse pelo vosso apoio incondicional! Amo-vos muito, estão para sempre no meu coração! Beijão grande!

425

Dr. Mireille van der Linden, it is such a joy each time I see you! Thank you for saving me in a period when I was so lost trying to survive as a Dutch clinician. You altruistically invested your own time to mentor me and teach me Dutch. You not only thought me Dutch, you made me feel welcome and hopeful. To this day you are an incredible supervisor, giving the best tips on how to communicate with patients! Everyone loves you! And I am no exception! Thank you so very much! I am forever grateful; you have no idea how much it meant to me. Dr. Jan Mekkes, thank you so very much for being the best opleider anyone can ask for. For always defending our interests so rightfully. For your endless patience and for sharing your humongous knowledge with us. For making us laugh with your sense of humor. For not being judgmental and allowing me to openly share my thoughts and concerns. Furthermore, even though I am an outlier, I thank you for never making me feel like one. To all other dermatologists from the Amsterdam UMC, thank you for your training, empathy and patience with this foreigner with a thick (sometimes non-understandable) accent. Thank you for all you have taught me and for supporting me during my Ph.D. To all my GGD colleagues, thank you so very much for the wonderful, fun and inspiring time that I had while working with you at the GGD Amsterdam. I was always so happy to go to work, and it was one of the best working experiences I ever had. I miss it! Thank you for the vote of confidence; my first Dutch job and the opportunity to practice Dutch with the patients. I have so much respect and love for you all! Thank you! Meghan, I was so very lucky to have had the opportunity to join you as a roommate in the beautiful and wonderful apartment at Melrose 31th. I loved every second we lived together. It was in every way perfect! You really made my time in Boston unforgettable! I miss those days very much! I miss you! You will always be in my heart! THANK YOU! My Boston Family, Paulo Branco, Lisa, Fallan, PJ, Mark, Dana, Everly, Luke and Lila, thank you SO VERY much for hosting me without any reservations, even without having met me before. You made sure I felt home, safe and welcomed; from the moment I landed in Boston. Furthermore, you also helped my friends/colleagues. You embraced me into your family and provided me with numerous unforgettable moments. I will forever remember your hugs, our laughs, the delicious food (including the legendary Pig roast) and the many moments we shared together. You are a beautiful and very strong family. I am so proud to be part of it! Love you all! Thank you!

All my incredible friends in Boston – Josephine, Mark, Jan-Willem, Sjors, Hannah, Bote, Klaas, Thomas, Pim, Maaike, Lauren, Lisa, Dominique, Ana, Ines, Joana, Mariana and many others. I will never forget the many adventures and fun we had together. I only wish we would see each other more often. Thank for all your support and for making it an unforgettable experience! Pieter en Wijnand, you made my time in Boston magical! We had so much fun together! From P-town, Upstate New York, Club café, Paradise, snow-ball fights, many diners and even introducing me to Pieter! I am so grateful for all the love and support that you gave me ever since, both in Boston and in Amsterdam! You are extraordinary friends! Thank SO you very very much! Aos meus irmãos do coração, Dany, Flávio e Manuel: Quem diria que após tantos anos estaríamos cada vez mais inseparáveis. Mesmo vivendo em 4 países diferentes, estamos cada vez mais próximos. Vocês sempre me ajudaram, apoiaram, mas acima de tudo dão-me tanta alegria e risos, sem qualquer criticismo. Aconteça o que acontecer sei que me ajudarão sempre no que for preciso (como o têm feito). Adoro-vos muito, e como sempre mal posso esperar para estarmos novamente juntos!!! Muito, muito obrigado meus irmãos!!! Minha adorada família de Santa Maria, Tias, Tios e Primos, desde pequenino que me recebem de braços abertos, me acompanham em tudo e me dão todo o vosso carinho. Obrigado pelos divertidos Natais e férias maravilhosas que sempre me proporcionaram. Amo-vos muito muito! Tia Zina, José, Kenley e Wendy, muito obrigado pelo afeto, supporte e dedicação que me dão continuamente. Sei que posso sempre contar convosco. Amo-vos tanto tanto! Quem me dera que estivessemos mais perto! Minhas lindas avós, Iva e Marta, estou-vos muito grato por tudo o que vocês me ensinaram. Pelo amor que me dão. Sempre a tentar seguir os vossos conselhos, amo-vos muito. Rita, Catarina, Filipa, Cláudia, Iolanda, Daniela, Inês, Micaela e Joana, muitíssimo obrigado pela vossa amizade! Após tantas aventuras conjuntas, vocês são como família! Sem duvida que eu não teria alcançado esta etápa se não fosse pelo vosso apoio incondicional! Amo-vos muito, estão para sempre no meu coração! Beijão grande!

426

Charlotte and Sofia, our friendship started many years ago, way before the Ph.D. We have met endless times, gone through life changing adventures and you have supported me in every crazy phase of my life. Thank you for your loving and caring friendship! Edo, I was thrilled to move in as your housemate! You are such an incredible person, so positive, caring and funny! Sorry that I have been so busy, and we haven’t had much roommate social time together. Thank you for your understanding and support. Thank you for the laughs and great moments we already had together… but mostly for always making me feel at home! Now that the Ph.D. is done, let’s have lots of fun!! And Joakim, you too are joining us! So happy to have met you and have you as a friend! Gwen, Sijia and David, you have been great friends since we met during the immunology course! We always have a great time together – mostly while cooking together. More importantly, we share the same immunological research-related struggles or residency-struggles. We speak the “same language”, fully understand one another and truly value each other’s achievements. Thank you for your help, incentive and friendship all the way! Ana Helena e Daniel, eu tenho tantas saudades vossas! Eu era muito mais feliz quando tinha vocês aqui perto de mim! Estavam sempre prontos e dispostos a ajudar. Vocês são umas das melhores pessoas que eu conheço. Muito muito obrigado por todo o apoio que me deram, por me deixarem dormir no vosso sofá quando me esquecia das minhas chaves em casa, pelos inúmeros jantares deliciosos e maravilhosos momentos que passamos juntos. Obrigado pelos vossos concelhos, apoio e amizade! Joel, Sander, Kornelis, Mark, Bas, Timothy & Jonas, you have been the greatest group of friends! We have had so many great moments together. Thank you for your support, for the patience to listen to me talk about my work and T cells. But mostly for making my experience in the Netherlands so joyful and unforgettable! Sylvester, you have been such a crucial friend! You are always so positive, spontaneous and joyful! I always have the best time when I am with you. Thank you very much for always being there for me. For continuously making sure I was doing well. For always picking up the phone and listening patiently to me at crucial times. For your caring and understanding support. I am so lucky to have you as a close friend! Thank you so very much!

Kenneth, you became very easily one of my best friends! Meeting you completely changed my experience in the Netherlands. Living and working in Amsterdam immediately became so much more joyful and exciting! We have experienced incredible adventures … and it is only the beginning… Thank you so very much for being the best friend anyone could ask for. For always being there for me, both in the hard and joyful moments. Your energy, positivity and fierceness are an inspiration! Thank you so very much for supporting me in every way throughout this journey! My beloved Dutch family, Lidwien, Maarten, Dorien, Tim, Max, Martijn, Lesley, Philip, Boris, Marij, Frans, Charles, Carla, Hanneke and extended family, you made this entire journey possible! I wouldn’t be here without your humongous support! From the very first moment that I met every one of you, you made me feel like a member of your family. You were always so excited and welcoming, even before I knew if I could move to the Netherlands. You made incredible sacrifices to make me feel at home. Lidwien, você estudou Portugês durante longos meses, ao Sabado - no seu tempo livre! Não há nada mais carinhoso e nobre. Você é incrível, amo-te muito! Jullie hebben voor altijd een plekje in mijn hart en blijven gevoelsmatig voor altijd mijn Nederlands familie. Jullie hebben mijn geweldig ondersteund met integreren tijdens een hele moeilijke overgang van Boston naar Nederland. Maar dankzij jullie leerde ik van Nederland te houden, waardoor ik hier graag wil bijven. Ik ben jullie voor altijd dankbaar en ik houd heel erg van jullie! DANK JULLIE WEL!! Querida família do Algarve: Ilda, Henrique, Mara, Stella, Ricardo, Maria Inês, Simão: Vocês sempre me apoiaram nos momentos mais difíceis e importantes da minha vida. Mas acima de tudo, quotidianamente fazem parte da minha vida. Eu mal posso esperar para estar de novo convosco. Fazem-me rir que nem um tolo, e dão-me amor por quem sou. Tenho sempre muitas saudades vossas! Ilda: muito mas muito obrigado pela tua paciência ternura e amor ilimitado. Primeiro por me manteres vivo e dares-me de comer. Segundo por me deixares brincar sem restrições. E por último pela gigantesca paciência em me ensinar, quando eu detestava estudar. Foste e és a minha inspiração no que sou e quero ser. Ao meu afilhado, José Miguel: um grande abraço especial. Muito obrigado pela alegria que sempre me dás, pela empatia que temos. És o meu grande orgulho!

427

Charlotte and Sofia, our friendship started many years ago, way before the Ph.D. We have met endless times, gone through life changing adventures and you have supported me in every crazy phase of my life. Thank you for your loving and caring friendship! Edo, I was thrilled to move in as your housemate! You are such an incredible person, so positive, caring and funny! Sorry that I have been so busy, and we haven’t had much roommate social time together. Thank you for your understanding and support. Thank you for the laughs and great moments we already had together… but mostly for always making me feel at home! Now that the Ph.D. is done, let’s have lots of fun!! And Joakim, you too are joining us! So happy to have met you and have you as a friend! Gwen, Sijia and David, you have been great friends since we met during the immunology course! We always have a great time together – mostly while cooking together. More importantly, we share the same immunological research-related struggles or residency-struggles. We speak the “same language”, fully understand one another and truly value each other’s achievements. Thank you for your help, incentive and friendship all the way! Ana Helena e Daniel, eu tenho tantas saudades vossas! Eu era muito mais feliz quando tinha vocês aqui perto de mim! Estavam sempre prontos e dispostos a ajudar. Vocês são umas das melhores pessoas que eu conheço. Muito muito obrigado por todo o apoio que me deram, por me deixarem dormir no vosso sofá quando me esquecia das minhas chaves em casa, pelos inúmeros jantares deliciosos e maravilhosos momentos que passamos juntos. Obrigado pelos vossos concelhos, apoio e amizade! Joel, Sander, Kornelis, Mark, Bas, Timothy & Jonas, you have been the greatest group of friends! We have had so many great moments together. Thank you for your support, for the patience to listen to me talk about my work and T cells. But mostly for making my experience in the Netherlands so joyful and unforgettable! Sylvester, you have been such a crucial friend! You are always so positive, spontaneous and joyful! I always have the best time when I am with you. Thank you very much for always being there for me. For continuously making sure I was doing well. For always picking up the phone and listening patiently to me at crucial times. For your caring and understanding support. I am so lucky to have you as a close friend! Thank you so very much!

Kenneth, you became very easily one of my best friends! Meeting you completely changed my experience in the Netherlands. Living and working in Amsterdam immediately became so much more joyful and exciting! We have experienced incredible adventures … and it is only the beginning… Thank you so very much for being the best friend anyone could ask for. For always being there for me, both in the hard and joyful moments. Your energy, positivity and fierceness are an inspiration! Thank you so very much for supporting me in every way throughout this journey! My beloved Dutch family, Lidwien, Maarten, Dorien, Tim, Max, Martijn, Lesley, Philip, Boris, Marij, Frans, Charles, Carla, Hanneke and extended family, you made this entire journey possible! I wouldn’t be here without your humongous support! From the very first moment that I met every one of you, you made me feel like a member of your family. You were always so excited and welcoming, even before I knew if I could move to the Netherlands. You made incredible sacrifices to make me feel at home. Lidwien, você estudou Portugês durante longos meses, ao Sabado - no seu tempo livre! Não há nada mais carinhoso e nobre. Você é incrível, amo-te muito! Jullie hebben voor altijd een plekje in mijn hart en blijven gevoelsmatig voor altijd mijn Nederlands familie. Jullie hebben mijn geweldig ondersteund met integreren tijdens een hele moeilijke overgang van Boston naar Nederland. Maar dankzij jullie leerde ik van Nederland te houden, waardoor ik hier graag wil bijven. Ik ben jullie voor altijd dankbaar en ik houd heel erg van jullie! DANK JULLIE WEL!! Querida família do Algarve: Ilda, Henrique, Mara, Stella, Ricardo, Maria Inês, Simão: Vocês sempre me apoiaram nos momentos mais difíceis e importantes da minha vida. Mas acima de tudo, quotidianamente fazem parte da minha vida. Eu mal posso esperar para estar de novo convosco. Fazem-me rir que nem um tolo, e dão-me amor por quem sou. Tenho sempre muitas saudades vossas! Ilda: muito mas muito obrigado pela tua paciência ternura e amor ilimitado. Primeiro por me manteres vivo e dares-me de comer. Segundo por me deixares brincar sem restrições. E por último pela gigantesca paciência em me ensinar, quando eu detestava estudar. Foste e és a minha inspiração no que sou e quero ser. Ao meu afilhado, José Miguel: um grande abraço especial. Muito obrigado pela alegria que sempre me dás, pela empatia que temos. És o meu grande orgulho!

428

My paranimfen, Sjors and Josephine (my twin), Thank you for your indispensable help throughout my entire Ph.D. Since we met in Boston, it was clear that we had so much in common. I admire how besides being excellent physicians, you studied at Harvard Medical School and Oxford University, do ground-breaking research, get prestigious grants, fellowships and awards, found companies, take on numerous managements, leadership or management roles at McKinsey or Third Rock ventures, and still find time to enjoy life, have partners and run marathons!!! Still, it is never enough, and you keep on seeking the next grandiose adventure! I am so very happy to have you as my friends, my paranimfen and as an inspiration to me! I am so so proud of you! Thank you for always being there for me, for your support and for pushing me to go the extra mile! Lieve Pieter, bedankt voor de eindeloze ondersteuning van de afgelopen 6 jaar. Ik zou hier nu niet zijn, niet naar Nederland zijn verhuisd, deze promotie niet hebben gedaan en niet in opleiding zijn gegaan was het niet voor jou. Niemand weet beter dan jij hoe moeilijk het was, en niemand heeft me zoveel geholpen als jij: op persoonlijk en sociaal niveau, met het Nederlands, de opleding, de promotie, het onderzoek en de verschillende loopbaanprojecten. Thank you very much for your support, compassion, strength, patience and understanding. You forced me to see the light when all seemed dark. You made sure to celebrate every triumph, big or small. I admire your positivity, spontaneity and the passion you have for your work! I am forever grateful for the many flawless, exotic, delicious and adventurous holidays that you planned for us, forcing me to have a break from work and recharge batteries. THANK YOU for the wonderful journey! Now, let’s Happy dance to this moment! Meus queridos pais, Armelim e Maria José, muitíssimo obrigado pelo continuo apoio. Eu sei que não tem sido nada fácil para vocês, porque estou longe e tenho mudado de país para país... não segui a minha carreira de forma tradicional, continuamente em novas aventuras mudando frequentemente de trajetória e de ideias. Obrigado por me apoiarem nesta que tem sido uma viagem turbulenta. Obrigado pela vossa paciência e apoio mesmo quando não percebem ou quando têm as vossas dúvidas. Obrigado por me incentivarem a estudar quando não queria, e fazer-me ver que o sucesso só é possível com muito trabalho e perseverança. O meu êxito só é possível graças aos melhores pais do mundo! Muitíssimo Obrigado! Amo-vos muito muito!!! Sou feliz graças a vocês Meu Amorzão, Martolas, tu és uma das minhas maiores alegrias. Muito obrigado por toda a tua paciência, ajuda e apoio incondicional. Sei que posso contar sempre contigo e adoro cada momento que estamos juntos. Amo-te tanto! Obrigado pela Pessoa que és e o que significas para mim. Tu és parte de mim. Amo-te muito muito muito!