Skin-Resident Dendritic Cells Are KeyElements of the Skin Immune System

The skin represents a natural barrier withthe ability to respond to foreign stimuli /anti-gen (Ag) with innate and/or specific immuneresponses. Accordingly, the skin is a highlyimmunogenic organ wherein both epidermaland dermal strata contain a complete comple-ment of cell types and pro-inflammatory

mediators that initiate and regulate the out-come of innate (inflammatory) and adaptive(specific) immune responses, while main-taining the tissue homeostasis characteristicof the steady state (1,2).

Epidermal cells with proinflammatory andimmune regulatory functions include ker-atinocytes, melanocytes, Merkel cells, and thepopulation of epithelial dendritic cells (DC)[Langerhans cells (LC)]. The dermal immune

AbstractThe skin functions as an important pro-inflammatory and immuneorgan. Accordingly, the epidermis and dermis are highly populatedby dendritic cells (DC), which are potent antigen-presenting cells(APC) with important immunostimulatory and migratory activi-ties. Whereas the biological characteristics and immunologicalfunctions of epidermal DC known as Langernahs cells (LC) havebeen the focus of intense research in the past, less is known regard-ing their dermal counterparts named dermal dendritic cells (DDC).Although it has been widely accepted that LC are the more rele-vant skin-resident APC, recent experimental evidence challengesthis concept and proposes a different role for these important cellpopulations. In this article we compile recent scientific advancesregarding the function of different skin-resident DC and we try toreconcile the new observations with the previously establishedparadigm.

Key WordsSkin immune systemDendritic cellsLangerhans cellsDermal denritic cellsC-type lectinsCD1Dendritic cell precursorsCD14

Dr. Adriana T. LarreginaSuite 145 Lothrop Hall,190 Lothrop Street,Pittsburgh, PA 15213, USAE-mail: adrianal@pitt.edu

127© 2006Humana Press Inc.0257–277X/(Online)1559-0755/06/36/1–3:127–136/$30.00

Professional Antigen-Presenting Cells of the Skin

Immunologic Research 2006;36/1–3:127–136

Alicia R. MathersAdriana T. Larregina

Departments of Dermatology andImmunology, University ofPittsburgh School of Medicine,Pittsburgh, PA

system includes dermal dendritic cells(DDC), macrophages, endothelial cells, andmast cells, and both epidermis and dermiscontain αβ and γδ T lymphocytes (the lattermore prominent in mouse). In addition to cel-lular elements, the epidermis and dermiscount with a vast network of regulatorycytokines, neuropeptides, and hormones witheither pro-inflammatory or anti-inflamma-tory activities, which contribute to the initia-tion and control of skin-related inflammatoryand immune responses (1,2).

Dendritic cells from the myeloid lineageare unique Ag-presenting cells (APC) residentin peripheral tissues with the abilities of (i)taking up and processing Ag, (ii) migratingand transporting Ag from periphery to sec-ondary lymphoid organs, and (iii) stimulatingnaïve T cells (3). According to these criteria,epidermal LC and DDC represent the mainpopulations of myeloid professional APC res-ident in the skin (4).

The understanding of the biology andfunction of LC and DDC is of particularinterest to the field of immunology for pur-poses ranging from immunization to toler-ance induction. Indeed several vaccinationand immune therapy approaches utilize theskin as a platform for Ag delivery (5). Con-versely, the presence of skin DC represents amajor obstacle for the purpose of skin andbone marrow allogeneic- (allo-) transplantsbecause skin DC are essential for initiation ofallo-transplant rejection and for the develop-ment of graft-vs-host disease (GVHD) (6,7).Similarly, skin-resident DC are implicated inthe etiology of undesired skin immune–baseddisorders such as atopic dermatitis, contactdermatitis, and psoriasis (1). Together theseobservations explain current efforts focusedon a better understanding of the regulation ofthe immunogenic and tolerogenic functionsof skin-resident DC.

Although the mechanism(s) regulating thebalance between maintenance of peripheralself-Ag tolerance vs induction of immuneresponses by skin DC is (are) not completelyelucidated, it is accepted that during the steady-state intermediate mature DC, resident in theskin, mobilize via lymph transporting self-Agand presenting those Ag to T cells in a tolero-genic manner (8,9). Interestingly in the steadystate, two populations of epidermal LC havebeen identified according to the expression ofthe MHC class II molecules, MHC-IIlow andMHC-IIhigh, the latter probably representing apopulation of LC that have undergone somelevel of activation and are ready to start migrat-ing to the skin-draining lymph nodes (sDLN)(10). Conversely, if a foreign Ag penetrates theskin in the presence of an inflammatoryresponse (with secretion of the pro-inflamma-tory mediators IL-1β, TNF-α, IL-6, and PG-E2,among others), skin DC undergo phenotypematuration, they rearrange their cytoskeletonand they migrate to sDLN to initiate an Ag-spe-cific stimulatory response (11). A detaileddescription of the mechanisms regulating DCmaturation and skin emigration has been exten-sively reviewed and exceeds the scope of thisarticle. Here we will focus on the T cell stim-ulatory function exerted by LC, DDC, and thepopulation of CD14+ DC precursors that residein normal human skin and has been the centerof our studies during the last years.

Langerhans Cells and Dermal DendriticCells: Similar or Different?

Distinguishing the immune regulatory func-tions exerted by LC and DDC is highly relevantfor the purpose of vaccine development,immunotherapy of tumors, transplant rejection,and autoimmunity. However, in vivo identifi-cation of whether LC and DDC have similaroverlapping or rather opposite functions has

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been extremely problematic due mainly to theconstant changes in phenotype and functions ofthese DC with high plasticity and to the lack ofappropriate experimental models.

As APC resident in the skin, LC and DDCshare phenotypic and functional characteris-tics. As leukocytes from the myeloid lineageboth LC and DDC express CD45RO, CD13,and CD33 and they are negative for other lin-eage specific markers such as CD3, CD19,CD20, CD16, and CD56 (2). As potent APCboth LC and DDC are characterized by (i)expression of high levels of major histocom-patibility complex class- I (MHC-I) andMHC-II molecules, (ii) expression of DC–Tcell adhesion and co-stimulatory molecules,(iii) ability to internalize and process proteinand glycolipid Ag, (iv) high migratory capac-ity, which allows them to transport Ag fromperiphery to sDLN, and (v) strong allo–T cellstimulatory function (3,4).

On the other hand, and due to their highplasticity, LC and DDC adapt to their microen-vironment and express a differential set ofmolecules. Accordingly, epithelia-resident LCexpress e-cadherin that mediates their adhe-sion to keratinocytes and they have membraneadenosine triphosphatase (ATPase), whichinactivates ATP molecules released in theepidermis (4,12,13). The DDC counterpartsexpress a different set of enzymes than LCincluding nonspecific estearase, β-glu-curonidase, acid phosphatase, and intracyto-plasmic transglutaminase clotting factor XIIIa(FXIIIa), and they do not express e-cadherin(14,15).

Recently, LC have been distinguished fromDDC by the expression of different C-typelectins (mouse and humans) and CD1 mole-cules (humans), which are involved in cellu-lar internalization and presentation ofglycolipid Ag to T cells, respectively. BothLC and DDC express the C-type lectin DEC-

205 (CD205); however, the expression of lan-gerin is restricted to LC and their precursors.Conversely, DDC and not LC express themannose receptor [MMR (CD206)] and thedendritic cell–specific intercellular adhesionmolecule 3 grabbing nonintegrin molecule[DC-SIGN (CD209)].

LC and DDC express different types of theCD1 Ag-presenting molecules, only LCexpress CD1a (humans) and only DDC expressCD1b (human) and CD1d (mouse and human)(4). Ultrastructurally, LC are characterized bythe presence of the Birbeck granule (BG),which is a subdomain of the endosomal recy-cling compartment induced after interaction oflangerin molecules with specific ligands (16).Langerin, BG, and CD1a molecules function ina coordinated way for the uptake, processing,and presentation of glycolipid Ag. CD1a mol-ecules that are internalized into BG are loadedwith microbial glycolipids endocytosed vialangerin molecules (17). The binding of gly-colipid Ag to CD1a molecules does not requireacidification in the endocytic cell compartment(18). Most of the glycolipid Ags that are pre-sented in the context of CD1a are moleculesfrom the cell wall of mycobacterium [i.e.,mycobactin from Mycobacterium tuberculosis(19)] and mycolyl arabinogalactan peptido-glycan (MAGP) from M. leprae] (17). Specificblockade of langerin prevents the cellularinternalization of MAGP and impairs prolifer-ation of MAGP-specific T cells. In addition,langerin molecules are involved in the inter-nalization of carbohydrates containing N -acetil-glucosamine and mannose into BG (20).

Different from LC, DDC internalize gly-colipids via mannose receptors (CD206) andDC-SIGN (CD209) and they are sorted intothe endocytic pathway. In the late endo-somes/lysosomes of DDC, glycolipids co-localize with CD1b molecules, which resultsin loading of CD1b groves with Ag (21).

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CD1b molecules bind to lipoarabinomannan(LAM), phosphatidylinositol mannoside, andglucose-monomycolate (GMM) present in thecell wall of mycobacteria (22). DDC are theonly skin-resident APC that express CD1dmolecules (23). CD1d molecules present theglycosphingolipid α-galactosilceramide(αGalCer) to CD1d-restricted NK T cells(24). Activation of NK T cells through CD1dresults in production of IFN-γ favoring cellu-lar immune responses (22). The observationthat both LC and DDC express a different pat-tern of molecules involved in the uptake andpresentation of glycolipid Ag might representa complementary rather than an oppositefunction of these two APC resident in differ-ent skin strata.

Upon activation and skin migration, LCloose BG and downregulate the expression ofCD1a, langerin, and e-cadherin on their cellsurface, which makes it difficult to distin-guish skin-migratory LC from DDC (25–27).Regardless of these DC maturation changes,in humans, detection of the expression ofintracellular langerin and low levels of mem-brane CD1a by LC and expression of FXIIIaand CD1b by DDC allow distinguishing LCfrom DDC. Regarding the mouse model, thephenotypic distinction of LC from DDC hasbeen more difficult than in humans. Althoughdetection of intracellular langerin is particu-larly useful to differentiate LC from DDChoming in the skin, the characterization ofthese two DC populations in sDLN is moreproblematic due to the fact that other DChoming in secondary lymphoid tissues,express langerin. Thus, a more accurate iden-tification of skin-homing DC in sDLN cellsrequires using a combination of markers todetect the simultaneous expression ofCD11c, CD11b, MHC-IIhigh, DEC-205, andintracellular langerin. Whereas CD11c is aspecific marker for mouse DC, detection ofCD11b establishes the DC myeloid lineage.

High expression of DEC-205 and MHC-IIfavor their skin origin and the presence ofintracellular langerin is useful to distinguishLC from DDC.

T Cell Stimulatory Functions of LC and DDC

The early stages of DC–T cell interactionare crucial to determine the outcome of thefuture immune response or to maintainperipheral self-tolerance. In the steady state,immature/semimature DC trafficking consti-tutively from peripheral tissues to secondarylymphoid organs are believed to be responsi-ble for the maintenance of peripheral T celltolerance. Although the mechanisms involvedin the maintenance of peripheral self-toler-ance are not fully understood, it is possiblethat DC might exert tolerogenic function byinducing anergy/apoptosis of naïve T cellsand /or by favoring the generation of a popu-lation of T cells with regulatory function (reg-ulatory T cells: Treg) (28).

Conversely, DC that have matured inresponse to pro-inflammatory mediatorsand/or signaling through pathogen associatedmolecular patterns (PAMP) are responsiblefor activation/polarization of T cells. Duringthis time, immunostimulatory DC have theability to induce the differentiation of naïveCD4+ helper T (Th) cells into Th1/Th2 cellsor to activate cytotoxic CD8+ CTL intoTc1/Tc2 cells to eliminate tissue-infected ortumor cells (2,5). Secretion of IL-12p70 andIL-4 by DC induces differentiation of Th1 andTh2 cells, respectively, whereas release of IL-10 and TGF-β1 in the absence of other pro-inflammatory cytokines is associated withgeneration of Treg cells (2,5).

The traditional paradigm establishes thatboth LC and DDC are potent APC with simi-lar abilities to stimulate strong T cell immuneresponses to tetanus toxoid, microbial, andallo-Ag and to trigger delayed-type hyper-

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sensitivity. Thus, we have taken for grantedthat both populations of skin-resident DC areable to efficiently activate CD4+ Th cells aswell as CD8+ CTL (29). However, recentstudies have demonstrated that under certainconditions LC and DDC might not act as themain APC population for the priming andactivation of CD8+ T cells after viral infection(30). Indeed, it has been suggested that someof the immune stimulatory functions attrib-uted in the past to LC are accomplished byother DC populations including (i) plasmacy-toid DC (pDC), (ii) inflammatory dendriticepidermal cells (IDEC), (iii) blood-borneCD8+DC, and (iv) DDC.

Different from myeloid LC and DDC, plas-macytoid DC express a broader pattern ofToll-like receptors and secrete high amountsof type I IFNs, which are crucial for thedevelopment of antiviral responses (31–33).Epidermal IDEC that secrete IL-12p70 seemto be the main effectors in skin chronicinflammatory diseases (34–36). Regardingpresentation of viral Ag proteins, it has beendescribed that cross-priming or cross-toler-ization of CD8+ CTL is an exclusive functionof the population of blood-borne CD8α+ DCresident in secondary lymphoid organs(30,37) and is not a function of skin-derivedDC. Finally, recent experimental data suggestthat DDC are the main skin DC populationwith immunostimulatory function, whereasLC exert an immune regulatory/tolerogeniceffect. Indeed, it has been demonstrated thatDDC induce a stronger delayed type hyper-sensitivity responses than LC, and that DDCbut not LC are able to generate protective Th1responses to herpes simplex virus-2 and leish-mania (38–43).

Together this recent evidence challengesprevious paradigms that positioned LC as themain immunostimulatory APC of human andmouse skin. As a result, several new questionshave emerged regarding the APC functions of

LC and DDC such as whether (i) they displaya different T cell stimulatory function, (ii)skin DDC and not LC produce bioactive IL-12p70 to drive Th1 biased responses, or (iii)LC and not DDC might have a role in induc-ing T cell tolerance.

In order to reconcile new data with estab-lished paradigms, our laboratory has ana-lyzed the capacities of human LC and DDC toproduce IL-12p70 and to induce Th1-biasedimmune responses. For this purpose we usedpurified human-skin-migratory DC from epi-dermal dermal explants that represent an irre-placeable experimental model which allowsintercepting DC trafficking via lymphatic ves-sels from the skin toward sDLN. Our resultshave demonstrated that both LC and DDCmigrate as mature DC populations accordingto high expression of (i) Ag-presenting MHCclass I and class II molecules, (ii) DC–T cellco-stimulatory molecules CD80, CD86,CD40, and CD83, and (iii) the secondarylymphoid organ-homing molecule CCR7.

LC and DDC secreted a similar pattern andlevel of cytokines. Surprisingly, LC and DDCproduced IL-10, TGF-β1, and IL-23p19 andlow levels of IL-12/23p40, but they do notsecrete the bioactive IL-12p70. We deter-mined that the absence of IL-12p70 under ourexperimental conditions was not due to DCexhaustion or to protein degradation or to thelack of DC1 stimuli (44).

Regardless the lack of IL-12p70, both LC andDDC were able to induce effector/memory(CD45ROhi, CD62Llo, CCR7lo) IFN-γ secretingTh1 cells (44). The ability of LC and DDC tostimulate proliferation of naïve CD4+ T cellsdepended on the expression of MHC-II, CD11a,CD54, CD80, and CD86 by these DC becausespecific blockade of these molecules abrogatedT cell proliferation in a dose-dependent fashion.The Th1-biasing function of LC and DDCdepended on their ability to produce IL-23, andwas significantly decreased by specific blockade

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of IL-23p19 or IL-12/23p40. These resultsclearly demonstrate that both LC and DDChave a strong immunostimulatory function andare able to induce effector memory T cellswhen they interact with naïve CD4+ T cells.

Skin Resident CD14+CD1a– DendriticCells: Immature DC Precursors orTolerogenic DC?

Following either non-inflammatory orinflammatory migration of cutaneous DC, theepidermis and dermis should be repopulated.The origins of the DC precursors that repop-ulate the skin appear to depend on which typeof migration has occurred.

During steady-state migration three possi-bilities has been considered to explain repop-ulation of epidermal LC: (i) LC turnover isvery slow and the rare cells that die or emi-grate from the epidermis are replaced by slowdividing resident LC; (ii) LC are long livedand they do not need replacement; and (iii)dermis resident DC precursors will mobilizeto the epidermis and will differentiate intoLC. During inflammatory responses largenumbers of DC emigrate from the skin leav-ing the cutaneous tissue temporarily devoid ofDC. Under these circumstances skin is likelyrepopulated by a pool of CD34+ bone marrow(BM)–derived progenitors that will differen-tiate into LC and probably into DDC (2,4,45).

Based on their expression of CD1a andCD14, smiDC are classified as (i) CD1a+

CD14– LC, (ii) CD1a– CD14– DDC, and (iii)CD1a– CD14+ DC precursors (Fig. 1). Ourlaboratory has been focused on the study ofthe population of CD14+ cells that sponta-neously mobilizes from human skin explants.We have demonstrated that different fromperipheral blood monocytes, skin-residentCD14+ cells emigrate from the skin via lym-phatic vessels, they lack the expression of M-CSF receptor, express low levels of langerin,

and do not attach to plastic. After short-termculture in the presence of TGF-β1, these cellsacquire the phenotype, ultrastructure, and Tcell stimulatory function of immature LC, asdetermined by the high expression of CD1a,langerin, and e-cadherin, low/intermediateexpression of MHC-II, CD86, and CD40, andlack of CD14, and BG. Accordingly, theyexert low stimulation of naïve CD4+ T cells.After culture in GM-CSF and TGF-β1 orGM-CSF, TGF-β1 and IL-4, skin-migratoryCD14+ acquire a potent allo-stimulatory func-tion comparable to that displayed by LC orDDC. Thus, our experimental data favor thetheory that, at least under certain conditions,LC are repopulated by precursor cells thatreside in the underlying dermis and perhapsunder the appropriate conditions, yet to beidentified, these precursor cells have the abil-ity to differentiate into DDC (46,47).

Regardless of the ability of skin migratoryCD14+ cells to differentiate into potent DC, wecannot overlook the fact that these cells mobi-lize from the skin as immature DC and theyinduce a level of T cell proliferation similar tothat of circulating monocytes (48,49).Together these observations might lead us toassume that immature/semimature skin-migra-tory CD14+ cells might have a tolerogenicfunction as it was previously described for thepopulation of immature DC generated fromhuman peripheral blood monocytes (50). Toaddress this question we analyzed the abilitiesof skin-migratory CD14+ cells to producecytokines that might bias CD4+ Th cellresponses or to induce a population of Treg

cells. As it was previously reported character-istic of regulatory DC, CD14+ DC secretedhigher amounts of IL-10 and TGF-β1, loweramounts of IL-12/23p40, they have a lowernumber of mRNA transcripts for IL-23p19compared to LC and DDC, and they wereweak stimulators for allo-naïve CD4+ T cells(44). However, functionally, CD14+ cells were

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unable to generate Treg cells and they induceda population of responder T cells that pro-duced intermediate levels of both IFN-γ andIL-5, and did not secrete significant amountsof TGF-β1 or IL-10. Moreover and contrary toa tolerogenic function skin-migratory CD14+

cells became potent stimulators of allo CD4+

T cells and Th1-inducers when incubated athigh DC:T cell ratios, when they were co-cul-tured for longer periods of time with respon-der T cells, or when IL-23 was added to theMLR culture medium (44). Together these

observations strongly indicate that CD14+ DCrepresent semi-mature population of DC withpotential to develop into strong immunostim-ulatory APC.

Final Remarks

The understanding of the mechanismsemployed by the skin to determine betweenthe stimulation of immune responses vs main-tenance of tolerance needs further investiga-tion. Indeed, it is still controversial whether

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Fig. 1. Cell populations of skin migratory DC. (A and B) LC purified according to the expression of CD1a(A) and DDC purified as a double-negative CD1a/CD14 population (B), show cytology of mature DC withabundant membrane dendrites, and bean shaped nuclei. (C) Skin-migratory CD14+ cells (LC precursors) showthe characteristics of a more immature DC including fewer membrane dendrites and an abundant intracellu-lar vesicular compartment. May–Grunwald Giemsa. Original magnification, 500X. Bar: 5 µm. (D) Trans-mission electron microscopy demonstrating differentiation of CD14+ into LC after culture in the presence ofTGF-β1. CD14+ cells acquire dendritic membrane processes and Birbeck granules (inset). Original magni-fication, 5000X. Inset: 100,000X. Bar 3 µm.

the high plasticity, characteristic of myeloidDC, suffice to determine between immunity ortolerance induction, or if these two opposingfunctions are carried out by DC from differentlineages (i.e., myeloid, lymphoid, or plasma-cytoid DC). In addition, whether LC and DDChave redundant, complementary, or evenopposing functions has not yet been clarified.Our observations using the model of humanskin–derived DC strongly support the hypoth-esis that, owing to their high plasticity, skin-resident DC censor for foreign Ag but are stillable to maintain the homeostasis of the skin.Likely, LC and DDC adapt to the microenvi-ronment and present differential phenotypeaccording to where they are situated. Func-tionally, it is probable that most of the LC andDDC remain dormant during the steady statewhereas a low number gets activated andtransports self-Ag from the skin to sDLN topresent Ag in a tolerogenic fashion. In thepresence of inflammatory insult, LC and DDCmay have the ability to respond to the injuryand to mature into potent APC while still beingable to maintain tolerance to self-Ag.

Regarding the population of skin CD14+

cells, it is possible that they constitute dermalreservoir of precursors for cutaneous DCregeneration with the potential to differenti-ate into fully immunostimulatory DC. Theyalso migrate in a more immature stage duringthe steady state; however, little is knownregarding the immunological role these semi-mature skin migratory cells once they reachsDLN.

In summary the current study of theimmune functions of skin DC provides withmore questions than answers, and the under-standing of the mechanisms employed by theskin immune system to distinguish betweenthe induction of immunity or tolerance repre-sents a fascinating scientific challenge for theupcoming years

Acknowledgments

This work was supported by grants fromthe National Institutes of Health: NCI:R01CA100893 and NIAID: R21AI57958 toATL

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