tissue-specific contributions to control of t cell immunityt cell function is controlled in part by...

Tissue-Specific Contributions to Control of T Cell Immunity

Amanda C. Poholek

http://www.immunohorizons.org/content/5/6/410https://doi.org/10.4049/immunohorizons.2000103doi:

2021, 5 (6) 410-423ImmunoHorizons

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Tissue-Specific Contributions to Control of T Cell Immunity

Amanda C. Poholek

Division of Pediatric Rheumatology, Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA; and Department of Immunology,

University of Pittsburgh, Pittsburgh, PA

ABSTRACT

T cells are critical for orchestrating appropriate adaptive immune responses and maintaining homeostasis in the face of persistent

nonpathogenic Ags. T cell function is controlled in part by environmental signals received upon activation and derived from the tissue

environment in which Ag is encountered. Indeed, tissue-specific environments play important roles in controlling the T cell response to

Ag, and recent evidence suggests that tissue draining lymph nodes can mirror those local differences. Thus, tissue-specific immunity may

begin at priming in secondary lymph nodes, where local signals have an important role in T cell fate. In this study, we discuss the tissue-

specific signals that may impact T cell differentiation and function, including the microbiome, metabolism, and tissue-specific innate cell

imprinting. We argue that these individual contributions create tissue-specific niches that likely play important roles in T cell

differentiation and function controlling the outcome of the response to Ags. ImmunoHorizons, 2021, 5: 410–423.

INTRODUCTION

Adaptive T cell immunity begins when foreign Ag activates Tcells in the context of inflammatory mediators that indicatepathogenic insult to the organism has occurred. The moleculardetails of T cell activation have been the subject of much studyfor decades leading to the three-signal hypothesis that is nowaccepted as dogma. Furthermore, the individual contributionsof TCR signaling (signal 1), costimulation (signal 2), and cyto-kines (signal 3) to the activation, proliferation, and differentia-tion of effector T cells are well understood. The eventualoutcome of these three signals is transcription factor activationthat both alters the transcriptome by directly turning genes onor off, as well as modifying the epigenome, which has impor-tant effects on the differentiation potential and transcriptionalpathways of cells (1). The cytokine pathways that control thesedifferentiation decisions have been well described. Briefly, type1 responses occur in the context of IL-12, IL-27, and IFN-g;type 2 responses in the presence of IL-4, IL-13, IL-5, and IL-9;and type 17 responses in the presence of IL-6, IL-23, and IL-1b.

In addition to responses to infection, T cells play key roles incontrolling homeostasis, such as promoting regulatory T cell(Treg) populations in the presence of TGF-b, retinoic acid(RA), and IL-2 (2). Although the cytokine networks necessaryto drive T cell differentiation have been well described, severalstudies have found alterations in the T cell cytokine responseto the same Ag under different circumstances, such as the loca-tion or prior history of infection. These studies highlight thenotion that the context in which an Ag is encountered plays akey role in the ultimate fate that Ag will have on T cell differ-entiation. Collectively, we argue that these contextual signalsshould be considered in addition to signals 1, 2, and 3 and thatin vivo they may play key roles in shaping T cell differentiationand function.

Although much of our knowledge on T cell differentiationhas been carefully worked out using in vitro assays, this non-physiological system is inherently limited and lacks manyknown and unknown parameters in vivo, which likely contrib-ute to T cell activation and effector differentiation. Naive Tcells are activated in the secondary lymphoid tissues, where

Received for publication April 26, 2021. Accepted for publication May 17, 2021.

Address correspondence and reprint requests to: Dr. Amanda C. Poholek, 4401 Penn Avenue, Rangos Research Building, University of Pittsburgh, Pittsburgh, PA15224. E-mail address: [email protected]

ORCID: 0000-0002-5587-8940 (A.C.P.).

This work was supported by National Institutes of Health Grant R21AI156093-01.

Abbreviations used in this article: cDC, classical DC; DC, dendritic cell; FRC, fibroblastic reticular cell; HIF-1a, hypoxia-induced factor 1 a; LC, Langerhans cell; LN,lymph node; RA, retinoic acid; SCFA, short-chain fatty acid; SFB, segmented filamentous bacteria; Treg, regulatory T cell; Trm, tissue-resident memory T cell.

This article is distributed under the terms of the CC BY 4.0 Unported license.

Copyright © 2021 The Authors

410 https://doi.org/10.4049/immunohorizons.2000103

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ON THE HORIZON


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their initial differentiation and proliferation begins. The initia-tion of T cell activation occurs primarily in the T cell zone viainteraction with dendritic cells (DCs) (3). Activation of T cellsleads to changes in chemokine receptors that drive relocaliza-tion of cells within the lymphoid tissue or allow cells to exitthe lymph node (LN) and for the periphery (4). Activated CD4T cells will migrate to the T--B border, where they can interactwith Ag-presenting B cells. Successful interaction with a B cellcan drive CD4 T cell differentiation into T follicular helpercells, whereas some T cells take on Th1, Th2, or Th17 programsand migrate back to the tissues to mediate effector function.

How much of the programming decisions that drive a spe-cific effector subset occurs in the LN and how much occursupon return to the tissue site is still unclear; however, severallines of evidence point to the notion that sufficient program-ming in the LN occurs to impart initial programming to aneffector phenotype as well as instructions to return to the tissuespace where Ag was initially encountered. This is evident inthe barrier tissues such as the skin, gut, and lung, where tissue-derived factors drain to the LN and aid in programming T cellsto return to that tissue. For example, DCs from the lamina pro-pria express high levels of RALDH2, an enzyme that catalyzesthe conversion of the vitamin A metabolite retinol into RA. RA-producing DCs migrate to LNs, where they drive upregulationof a4b7 and CCR9 on T cells, which are critical for homingback to the gastrointestinal tract (5--7). Similarly in the skin,local IL-1 in the dermis drives potent production of IL-17 frommicrobial-specific ab T cells despite initial activation and dif-ferentiation to Th17 cells occurring in the draining LN via skin-derived DCs (8--10). Thus, although the tissues themselves area place to direct T cell effector function, tissue-derived factorsdraining to the LN create an extension of the tissue spacewhere specific instructions are imparted to T cells that shapethe earliest steps of tissue-specific immunity. We argue thenthat although the fundamental signals required for T cell acti-vation and differentiation are well understood, the impact oftissue-derived factors is only beginning to be appreciated for itscomplexity and diversity to impact T cell differentiation. In thiscommentary, we highlight the evidence that suggests tissuesplay a key role in shaping T cell responses in vivo and brieflysummarize potential factors that are likely to be critical forshaping tissue-specific adaptive immune responses. Many ofthese topics have been more extensively covered in comprehen-sive reviews that we highlight; however, the goal of this per-spective is to define the tissue-specific factors we believe arelikely to play important roles in T cell differentiation that havebeen overlooked as regulators of this process.

EVIDENCE FOR TISSUE-SPECIFIC ADAPTIVE IMMUNERESPONSES

Although in vitro studies have elucidated the operative path-ways and drivers of T cell activation and differentiation, in vivostudies provide evidence that adaptive immune responses can

vary in character depending on the route of immunization orinfection, suggesting tissue-specific factors play an importantrole in shaping the immune response. For example, bacterialinfection of the respiratory tract leads to IL-17--dominatedresponses, whereas other routes of infection skew toward aTh1 response (11--14). The i.v. or oral infection with Listeriamonocyotgenes produced an Ag-specific memory CD4 T cellpopulation that produced IFN-g upon restimulation, whereasintranasal infection promoted IL-17--producing memory CD4 Tcells (15, 16). These results were in line with reports that inha-lation of Francisella tularensis, which is associated with moresevere disease, drove increased IL-17 in comparison with themilder intradermal route of infection that promoted Th1responses, leading to increased bacterial clearance (17). Mecha-nistic studies have identified several factors in the lung thatsupport Th17 responses to infection, including PGE, TGF-b, IL-6, and IL-1b, indicating the lung environment promotes media-tors that support Th17 cells that may be absent in other tissuesettings (13, 14, 17). Vaccination studies have also reported thatthe route of immunization controls important outcomes of pro-tection, including altered Ab isotypes produced from i.m. (IgG)or aerosol (IgA) vaccination strategies (18, 19). In contrast, sys-temic, intradermal, or i.m. administration drives IL-12 fromDCs to promote Th1 cells (20--22). Thus, the character of theresulting T cell response can be altered, presumably because oftissue-specific factors that control the cytokine activity ofinnate cells present at the tissue site. Beyond bacterial infection,tissue-specific immunity is of particular importance in the gas-trointestinal tract, where the constant presence of the micro-biome requires regulatory control of T cell responses. T cellsresponding to commensals typically become Th17s or Tregs;however, in the presence of gastrointestinal infections, theseresponses can shift to Th1 cells, indicating that the change inenvironment can shape T cell differentiation (23). Responses tofood Ags also promote Tregs; however, intestinal infection canshift these in a similar fashion to commensal specific responses,potentially leading to long-term consequences such as celiacdisease (24--26).

In contrast, tissue-specific responses to allergens are morenuanced. Allergy is typically attributed to aberrant Th2responses, and allergic responses occur in a wide variety of tis-sues, including atopic dermatitis, allergic asthma, eosinophilicesophagitis, and food allergy. Our recent study highlighted thetissue-specific nature of Th2 cell differentiation in response toallergens via the transcription factor Blimp-1. Inhaled housedust mite drove Th2 cells in the lung via a Blimp-1--dependentpathway; however, s.c. injection of house dust mite extractdrove Th2 cells independently of Blimp-1 (27, 28). This was notspecific to house dust mite as similar results were achievedusing soluble egg Ag derived from Schistosoma mansoni worms.As Blimp-1 was required to indirectly promote GATA3, themaster regulator of Th2 cells, these results suggested that lung-specific immune pathways occur at the point of allergen prim-ing, possibly in the LNs draining the tissues.

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Indeed, tissue immunity is not limited to the tissue spacebut extends to the LNs draining those tissues. Oral tolerance iscritical for intestinal immunity, as the presence of food andmicrobial Ags creates a unique environment for the immunesystem to constantly survey and determine which Ags are path-ogenic and which Ags require tolerance. The initiation of oraltolerance occurs in the mesenteric LNs draining the gut andrequires delivery of Ag via DC transport (29). Oral tolerance isestablished by promoting Treg formation to commensal andfood Ags because of the presence of TGF-b and RA in the gut(30--33). In line with the notion of local induction of Tregs, thepropensity of T cells to form Tregs in the gut can be trans-ferred by surgical transplantation of mesenteric LNs from thegut to the popliteal fascia (34). In contrast, transfer of a periph-eral LN to the mesentery only partially increased Treg forma-tion even 8 wk posttransplant. Both the stromal compartmentand the indirect effects on the DCs played a role in altering Tcell differentiation toward Tregs, implicating the tissue space asplaying a key role in establishing a homeostatic niche thatremains in place even after transplant to a new tissue space.More recently, this idea has been extended to individual LNsthat drain different portions of the gastrointestinal tract (7),where tracking responses to OVA in different gut LNs lead toalterations in the outcomes of the T cell responses (35). Surgi-cal delivery of OVA Ag to distinct LNs lead to distinct out-comes in the percentage of Tregs or Rorgt1 Th17 cells formed.Furthermore, segmented filamentous bacteria (SFB)--specificTh17 cells were found in the colonic and inguinal LNs thatdrain regions of the gastrointestinal tract predominantly colo-nized by SFB, suggesting local colonization extended to theLNs draining those areas. Distinct transcriptional signaturescould be found in the stromal and DC compartments from dif-ferent gut LNs, suggesting that tissue-specific factors drainfrom the tissue site to the LN and set a homeostatic nicheunique to that tissue (7, 35). Taken together, these studies pro-vide ample evidence that T cell differentiation is impacted bythe tissue in which Ag is introduced. Furthermore, the tissueenvironment likely extends into the local draining LN, wherethe homeostatic experience of the tissue can influence the dif-ferentiation of T cells upon Ag encounter either to innocuousAg or upon infection with a pathogenic insult (Fig. 1). Althoughthere may be many unknown factors that contribute to thesetissue-specific niches, we highlight below several that areknown to or we believe are likely to impact T cell differentia-tion and should be considered when exploring the in vivo com-ponents shaping T cell adaptive immunity.

INTRINSIC CELLULAR POPULATIONS THATCONTRIBUTE TO TISSUE-SPECIFIC T CELLDIFFERENTIATION

Dendritic cellsDCs are a heterogenous population of innate cells that can bedivided into several functionally distinct groups that have been

extensively described in many excellent recent reviews (36--38).Briefly, DCs can be divided into conventional or classical DCs(cDCs), plasmacytoid DCs, monocyte-derived DCs, and Langer-hans cells (LCs). cDCs can be further broken into an LN resi-dent population and a migratory population that originates inthe tissue and subsequently drains to the LNs upon activation(36). Although their name implies their immovability, residentDCs can dynamically move within the LN, especially uponinfection (36, 39, 40). Ag introduced via tissues can either draindirectly to LNs, where it can be taken up and presented by resi-dent cDCs, whereas migratory cDCs directly sample andacquire Ag in the tissue. Studies suggest both populations ofcDCs engage in the T cell activation and differentiation process(36, 41, 42). Furthermore, both the resident and migratory cDCpopulations can be further divided into cDC1 and cDC2 cells.cDC1s preferentially induced Th1 responses and cross-presentto CD8 T cells, whereas cDC2s preferentially induce T follicu-lar helper and Th2 responses, although the mechanistic basisfor this delineation is not entirely understood (36, 43--48).Although there are key distinctions between cDC1 and cDC2cells, they both dynamically change upon infection or immuni-zation. The sensing of damage- or pathogen-associated mole-cules leads to inflammatory cytokine upregulation, increasedAg presentation, and costimulatory signaling ligands (49). Themigratory property of DCs to travel from the tissues to the LNis a critical part of DC function. Although CCR7 is a key recep-tor for all DC migration across tissues, tissue-specific migratorycues have also been described for skin, intestinal, and lung DCstrafficking to LN (40). It is important to note that comparisonof DC populations in tissues have identified unique tissue-spe-cific signatures associated with the tissue of origin (50). Thus,the precise tissue environment DCs originate from is likely toimpact not only how DCs migrate to their draining LNs butalso their precise function once there.

Many studies have explored the specific populations of DCsthat migrate from peripheral tissue sites to draining LNs in thecontext of homeostasis, infection, and immunization with Agsor allergens (40). Broadly, the specific DC populations at eachtissue site and unique functions associate with the tissue anat-omy, function, and interactions with the environment. Forexample, within the skin, dermal DCs and LCs both can takeup Ag and migrate to the draining LN; however, the kinetics bywhich they arrive vary, with dermal DCs arriving first and fol-lowed by LCs. In addition, the localization within the LN isaltered; LCs migrate to the paracortex, whereas dermal DCspreferentially reside in the interfollicular regions (51). Yet, bothLCs and dermal DCs carry Ag from commensals or pathogenswhere each DC population can play differential roles in pro-moting tolerance or induction of Th17, Th1, or Tregs, respec-tively (40, 46). Finally, migration of T cells back to the skin canpromote additional differentiation signals from skin-residentDC populations, further underscoring the different roles DCpopulations can play to support tissue-specific responses (9). Inthe gut, Ags from commensals and food are constantly sampledby lamina propria DCs that migrate upon inflammatory signals

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(52, 53). Importantly, lamina propria DCs preferentially pro-mote Treg generation via RA, likely because of the increasedlevel of nonpathogenic Ags in the intestine that require toler-ance induction (30, 31, 54). In contrast, mesenteric resident LNDCs do not have this same capacity (55, 56). More recently, theability to promote Tregs was demonstrated to be strongestfrom migratory cDC1 cells in the gut because of intestinal fac-tors such as thymic stromal lymphopoietin from epithelial cells,bile, and dietary retinoids (26, 57--59). This property can bealtered in the context of inflammation, driving T cells tobecome Th1 cells instead, suggesting the environmental contextof the gut on DC populations can influence the T cell response(23, 25, 60). Similarly, the lung has specific DC populations thatrespond to allergens and infection. Both cDC1s and cDC2s cantake up Ag and traffic to the mediastinal LN, yet cDC2s are

primarily associated with driving Th2 cells to allergens in thelung (61). More recently, inflammatory cDC2s were defined tobe driven by type I IFNs and important in both allergen andviral infection for promoting T cell responses (62). AlthoughcDC1s could promote CD8 T cell responses, inflammatorycDC2s could promote both CD8 and Th1 responses. In contrast,monocyte-derived DCs have limited migratory potential andability to activate T cells (62, 63). More direct evidence that tis-sue signals can alter T cell priming in the LN was shown in astudy assessing the role of TGF-b activation by migratory DCson skin tissue-resident memory cell formation (64). DCs lackingav integrin and unable to activate TGF-b, upon skin vaccina-tion, were unable to form effective tissue-resident memory Tcell (Trm) in the skin. This was due to epigenetic imprinting ofnaive CD8s in the draining LN, but not the spleen, indicating

FIGURE 1. Tissue-specific factors contributing to T cell immunity.

T cell differentiation is influenced by the interaction and direct signals provided by APCs but also by the surrounding environment (larger blue circle) in which

it sees Ag and becomes activated. This environment can be influenced by a myriad of factors (pink and green circles), leading to alterations in T cell differentia-

tion and function. External factors in the environment (green circles), including foreign Ags, the microbiome, and altered metabolic contexts, create tissue-spe-

cific homeostatic niches that are set early in life and can maintain a persistent state for surrounding cells, whereas cell types intrinsic to the organism (pink

circles) can be modulated by the environment to promote tissue-specific contexts during homeostasis and upon infection or pathogenic insult.




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that tissue-derived DC function to activate TGF-b prior to vac-cination creates a tissue-specific homeostatic niche that impactsnaive T cells even before they see foreign Ag to be primedtoward skin tissue-resident memory cells. Taken together, thesestudies of tissue-specific DC populations clearly demonstratethat DCs act as sentinels of the environment, migrate from tis-sues to LNs, and interact with T cells to shape their responsesboth in settings of homeostasis and in the context of infection.

Within the LN, there is additional organization beyond Tand B cell zones that shapes the T cell response. Studiesexploring DC migration have identified discrete micro nichesthat DCs localize to upon entry into the LN, suggesting DCsubsets fulfill important functions that require their localizationin specific areas of the LN, likely to interact with specific popu-lations of immune cells (3, 65). Several studies have now shownconvincingly that these DC niches play critical roles in T celldifferentiation. For example, DCs positioned in the interfollicu-lar zones located proximally to B cell zones seem to preferen-tially induce T follicular helper cell differentiation (66, 67).Furthermore, cDC1s and cDC2s have preferential localizationswithin the LN that contributes to differential location of Th1and Th2 cells within the LN. In one recent study, type I IFNsresulted in resident DC relocalization from the periphery to theT cell zone, whereas inflammatory monocytes were recruitedto form micro niches with the LN that played critical roles inearly T cell priming and effector differentiation (68). Anotherstudy found that type I IFNs altered the balance of CXCL9 andCXCL10 expression on DC and stromal cell subsets that haddistinct spatial locations in the LN that contributed to effectoror memory T cell generation (69). Although neither studyaddressed specifically the role of the tissue or examined differ-ent LNs, the formation of distinct niches within the LN indi-cates precise gradients of chemokines and cytokines playimportant roles in driving effector T cell differentiation andsmall perturbations in those signals, possibly derived from dis-tinct tissue sites can play a role in that process. Collectively,these studies imply that both the tissue in which the LN isdraining, as well as the micro niches that form within the LN,play critical roles in shaping the T cell response. As DC popula-tions are pivotal in both sensing changes in the environment,uptake of Ag, and migration to LNs to interact with T cells,they are likely to be highly flexible to precisely shape the T cellresponse needed depending on the situation.

Stromal cellsStromal cells play critical roles in LN organization and immuneresponses, as highlighted in several recent reviews (70--72). LNstromal cells comprise several populations, including fibroblas-tic reticular cells (FRCs), which are comprised of several sub-sets such as T zone reticular cells, follicular DCs that supportgerminal centers, marginal reticular cells, and medullary FRCs.In addition to FRCs, there are pericytes that surround bloodvessels, lymphatic endothelial cells, and blood endothelial cells(70). More recent single-cell studies of stromal cell populations

have indicated even more complex heterogeneity, suggesting alevel of specialization that aids in compartmentalizing theimmune cell niches of the LN as well as their responses toinsult (73). Upon infection or immunization, LNs expand insize in large part because of changes to stromal cells thatwork to accommodate the rapid proliferation and expansionof T and B cells as well as infiltration of DCs, macrophages,and other immune cells (70, 74). FRC changes in response toClec2--podoplanin interactions with DCs as well as prolifera-tion in response to inflammatory signals such as IL-1b, IL-17,TLRs, or type I IFNs that are key in supporting LN hypertro-phy and subsequent T cell responses (70). Thus, stromal cellsare important players in setting the environment for immuneresponses.

As stromal cells are noncirculating, they are likely the bestcandidates for driving persistent tissue-specific signatureswithin an LN. Indeed, a recent study exploring stromal andother structural cells in an organ-specific manner identifiedgene networks that were both cell type and organ specific thatshaped interactions with immune cells both at homeostasis andupon systemic infection underscoring the organ-specific natureof stromal cells and their influence on immune cells (75). Morespecifically, it has been well described that there is an increasedfrequency of Tregs in the mesenteric LNs draining the gastroin-testinal tract compared with other draining LNs. Several stud-ies exploring the mechanistic basis of this relative increasefound that transplanting the mesenteric LNs to the leg of themouse draining the footpad (popliteal fascia) retained theirability to preferentially induce Tregs even 50 wk posttransplant(34). The early presence of the microbiome after birth wasrequired for mesenteric LNs to promote Treg induction; yetonce introduced, ablation of the microbiome with antibioticswas insufficient to significantly alter the ability of the mesen-teric LN to promote Tregs (76). Isolation and transcriptomeanalysis of stromal cells from mesenteric LN and popliteal LNsconfirmed significant transcriptional differences in these twolocations that was not altered upon transfer. Intriguingly, how-ever, after transplant of mesenteric LN from germ-free mice tothe leg of specific pathogen--free mice, the transcriptomes ofstromal cells looked more similar to popliteal LNs than mesen-teric LNs, suggesting that once imprinted by microbial compo-nents in the gut, mesenteric LN stromal cells can maintain thissignature indefinitely even under different circumstances, yetunprimed stromal cells having never seen a microbiome arenow capable of being modulated by a new environment. Impor-tantly, these signatures also impacted DC populations, in partic-ular resident DCs. Interestingly, in the study mentionedpreviously looking at individual LNs from the gastrointestinaltract, stromal cell (FRC and lymphatic endothelial cell) isolationand transcriptome analysis from individual gut draining LNsdemonstrated gene level differences, again supporting thenotion that the stromal cells play a key role in creating thehomeostatic niche of individual LNs (35). Thus, these data sug-gest that the earliest experience of the environment is sufficientto imprint long-lasting tissue-specific signatures on stromal




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cells in LNs that can be maintained long term and subsequentlyinfluence T cell differentiation.

Nervous systemThe tissues are innervated by neurons that in addition to obvi-ous roles in motor function and sensation, are also in constantcommunication with immune cells (77--80). The neurons inbarrier tissues in particular play key roles in immune regula-tion, as they are constantly in contact with the environmentand can directly sense pathogens and noxious stimuli (77).Although these interactions are complex and are just beginningto be understood, several studies have already highlighted thecontextual nature of neuroimmune interactions on homeostasisand response to infection, suggesting tissue-specific differencesmay be key to subsequently shape the environment in waysthat may alter downstream T cell responses.

In the skin, Staphylococcus aureus infection is directlysensed by TRPV11 and Nav1.81 nociceptor neurons by N-for-mylated peptides and a-hemolysin toxin. In addition to pain,this triggers release of the neuropeptide CGRP, which reducesmonocyte influx, limits TNF-a production by macrophages,and limits the growth of draining LNs (81, 82). Similar mecha-nisms are operative in the lung in response to severe bacterialinfections, in which nociceptors can suppress gd T cells andneutrophils, limiting IL-17 responses and lethal pneumonia(83). Thus, neurons act to reduce inflammation induced byinfection. In contrast, fungal infection with Candida albicansdrives TRPV11 nociceptors to induce IL-23 from CD301b1 der-mal DCs, which subsequently act on gd T cells to produce IL-17 required for fungal clearance (84). In the gut, enteric neu-rons participate in host defense by secreting IL-18, which actson goblet cells to produce antimicrobial peptides and limit Sal-monella infection, whereas nociceptor neurons signal via CGRPto reduce the number of M cells that are critical for invasion ofSalmonella (85, 86). Similarly, parasitic infections of the guttrigger neuromedin U (NMU) neuropeptide production to acti-vate ILC2s, which can work via type 2 immunity to expel thepathogen (87, 88). In contrast, CGRP expressed by nociceptorneurons or ILC2s limits ILC2 activation as part of a negativefeedback loop limiting inflammation and inhibiting parasiteclearance (89). Thus, the neuroimmune cross-talk in the gutboth promotes host defense and protects from inflammation.

Recent studies have now extended the neuroimmune con-nection beyond the barrier tissues by demonstrating the pres-ence of both peptidergic nociceptor sensory neurons andsympathetic neurons directly innervating the peripheral LNsand impacting splenic immune responses (90, 91). In one studyexploring innervation of the LN, primary interactions wereidentified between sensory neurons and stromal cell compart-ments, suggesting activation of neurons likely influence LNcomposition and function, particularly in the context of aninfection or noxious stimuli. In addition, the splenic nerve, partof the sympathetic branch of the nervous system, was requiredfor T cell--dependent plasma cell formation to Ag (91). Choline

acetyltransferase (ChAT)--expressing T cells translated norad-renergic signaling from the splenic nerve to splenic plasmacells, although the effector status of these T cells was notexplored in this study. Collectively, these studies highlight thatneuroimmune modulation is highly contextual across tissuesites and likely depends on the tissue, type of neuron, type ofimmune cell, and type of stimuli involved. As the nervous sys-tem is highly innervated in barrier tissues that are constantly incontact with the environment as well peripheral LNs, neuronslikely constantly signal to the immune system to either suppressimmune responses and maintain homeostasis or promoteinflammation in the context of pathogen insult. In addition,they can limit inflammation in the context of infection to aid inrestoration of homeostasis. Therefore, it is highly likely thatneuroimmune interactions play key roles in promoting signalsthat contribute to T cell differentiation and effector function;however, the specific interactions between neurons and T cellsare limited, and this is an area of research that is likely to shapeour future understanding of T cell differentiation and functionin the future.

NONCELLULAR EXTERNAL FACTORS THATCONTRIBUTE TO TISSUE-SPECIFIC BIOLOGY

MetabolismIn addition to the tissue-specific cellular populations describedabove that can impact T cell differentiation, many external fac-tors can be present and influence in the tissue space. Altera-tions in metabolism are now well understood to be tissuespecific, and the role of metabolism on T cell differentiationand function has more recently come to be appreciated asdescribed in several reviews (92--96). Indeed, T cells can shifttheir metabolic capacity in settings of nutrient restriction or inan altered metabolic tissue environment to adapt accordingly.As T cells can migrate throughout the body, they must becapable of sensing changes in the metabolic environment andsubsequently adapt (96). These adaptations can include altera-tions of effector cell differentiation as well as survival and pro-liferation of their effector state. Early after activation, T cellsshift their metabolic state from mitochondrial oxidative phos-phorylation to aerobic glycolysis (97). In contrast, Tregs preferfatty acid oxidation even in a setting with excess glucose (93,98). Recent studies have profiled the metabolic state andcapacity of T cells in a variety of settings. Although manyin vitro studies have outlined key pathways controlling meta-bolic functions of T cells, evidence suggests in vivo things aremore complicated (99). The metabolic state of tissues is alsounique and dynamic, with varying combinations of nutrientsand signals that T cells must adapt to to proliferate, differenti-ate, and survive. Changes in the metabolic niche can have sig-nificant impacts on T cells and can alter activation, survival, oreffector differentiation (100).

Mitochondrial metabolism is critical for T cell activationand a key component of function (101). Although broadly




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thought to switch to aerobic glycolysis upon activation, effec-tor T cell reliance on oxidative phosphorylation in vivo maybemore heterogeneous than results described in vitro, suggestingadaptation to tissue environments might be key in controllingthis heterogeneity (99). In addition, differentiation of effectorCD4s use disparate components of the electron transportchain, as Th17 cells more heavily use complexes I and II,whereas Th1 cells required active complexes II and III (102).Limiting oxidative phosphorylation inhibits Th17 cells andalternatively promotes Tregs (103). Finally, memory cells relyon mitochondrial metabolism for their formation and mainte-nance as well as shift to use lipolysis and glycerol to maintaintheir survival (104, 105). In tumors, mitochondrial dysfunctiondriven by environmental signals such as continuous Ag stimu-lation and hypoxia promote loss of effector function(106--108). Thus, T cell differentiation and function rely onmitochondrial metabolism, and the tissue environments canplay important roles controlling the availability of metabolicinputs to fuel metabolism of the cells.

There are several metabolic conditions present in a varietyof settings in which T cells have evolved mechanisms of adap-tation. One common metabolic state is that of low glucose andhigh lactate, which is often found in solid tumors, inflamed tis-sues such as arthritic joints, atherosclerotic plaques, and in theadipose tissue of obese people. These inflammatory settings areones without pathogenic initiation and tend to be long-termstates of low-grade chronic inflammation. T cells in these envi-ronments of low glucose and high lactate undergo metabolicadaptations to use lactate rather than glucose for metabolic sur-vival. Tregs upregulate genes involved in lactate metabolism,enabling them to convert lactic acid into pyruvate, inhibitingaerobic glycolysis and supporting the metabolic preference foroxidative phosphorylation in Tregs, allowing them to maintaintheir suppressive function (109--111). In contrast to Tregs, effec-tor T cells are inhibited in the low-glucose and high-lactate set-ting of tumors, leading to reduced T cell activity (112--114). Yet,in the high-lactate conditions in settings of inflamed joints andafter increased exercise regimens, effector T cells couldincrease their capacity to endure high lactic acid concentrationsvia upregulation of lactate transporters or changes to their cen-tral carbon metabolism and remain functional or increase theirfunctional capacity to clear tumors (115, 116). Thus, for effectorT cells, the context in which the cells experience high lactatemay play a key role in whether function is inhibited or if cellscan rewire and adapt to their changing environment.

Hypoxia is another common state that T cells have mecha-nisms to adapt. Hypoxia, or settings of low oxygen availability,activate a specific transcription factor in T cells called hypoxia-induced factor 1 a (HIF-1a) (117). In settings of normoxia, oxy-gen-sensing proteins (PHD containing) inhibit HIF-1a by mark-ing it for degradation via ubiquitination. When oxygen levelsbecome low, HIF-1a becomes stable, translocates to thenucleus, and activates target genes and transcriptional path-ways that allow T cells to survive and function in the hypoxicenvironment. Loss of Vhl, the negative regulator of Hif1a in

CD8 T cells, leads to unrestrained effector cell differentiation,leading to excessive immunopathology and death postinfectionof chronic virus (118). Increased glycolysis and effector mole-cules suggested that in settings of hypoxia in which cells arenutrient limited, HIF-1a serves to boost metabolic pathways tomeet energy demands and impact important effector molecules(118). Hypoxia is often found in tumors in which glucose levelsare low because of the high glycolytic needs of the tumor itself.In tumors, hypoxia promotes metabolic dysfunction of T cellsby driving reactive oxygen species leading to increased phos-photyrosine signaling and NFAT localization to the nucleus andsubsequent T cell exhaustion (106). Thus, although T cells canadapt to hypoxic environments, altered nutrient environmentscan drive T cells into a state in which their function is some-what limited, suggesting multiple adaptations of T cell exist tomaintain survival in harsh metabolic environments.

Although changes in metabolism to meet the energeticdemands of the cell appear obvious, a less-appreciated, butlikely important, role for cellular metabolism are the metabolicbyproducts needed for epigenetic changes upon T cell activa-tion. Changes to metabolic pathways have consequences for theavailability of key metabolites, which are required for epige-netic modifications and transcription (119). The glycolytic cycleof activated T cells results in increased levels of acetyl-CoA anda-ketoglutarate. Glucose fuels the majority of acetyl-CoA pro-duction in proliferating cells, which is largely responsible foracetylation of cellular proteins, including histones (120).a-Ketoglutarate, another metabolite produced by glycolysis, isrequired for function of both DNA and histone demethylases(121). S-adenosylmethionine, a product of one-carbon metabo-lism, is a methyl donor for methyltransferases. Therefore, thereare many ways in which metabolic pathways of proliferatingcells intersect with epigenetic changes in cells. For T cells, thisis likely to be critical. Upon activation, T cells undergo rapidblasting and differentiation, indicating changes to the epige-nome are key in taking on the fate and function dictated by theenvironment. Yet, although the role metabolites play in the epi-genome are clear, as is the requirement for metabolic shiftsupon T cell activation, very few studies have linked the meta-bolic changes with the precise epigenetic changes that arerequired for T cell effector differentiation. This has been partic-ularly difficult to study in vivo in which metabolic changes inthe tissues may be the most important for linking metabolicchanges to epigenetic effects that impact the differentiation andfunction of T cells. Therefore, we hypothesize that tissue-spe-cific metabolic environments may play fundamentally key rolesin changing the differentiation and function of T cells in apotentially heritable manner, as changes that occur to the epi-genome has the power to be passed to future generations ofcells.

MicrobiomeThe microbiome is an important part of mammalian health andsurvival. As mammals evolved with microbes, a symbiotic




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relationship was established in which microbial communitiesare important for tissue development, metabolism, and hostdefense (122). Importantly, the gastrointestinal tract, skin, lung,oral cavity, and vaginal cavity each have completely uniquemicrobial communities. In fact, niches within the skin, such ashair follicles, as well as each distinct portions of the gut havedistinct microbial communities. These communities are alsodynamic, and changes in diet, habitat, systemic infection, orantibiotic use have been known to shift those communities(10). The diversity of the microbiome across tissue spacesimplies that there is local tissue compartmentalization and spe-cialization controlled by both the host and the microbiome thatis key both during homeostasis and under pressure from localinflammatory responses.

The ability of the microbiome to influence T cell differentia-tion is evident in many studies that have assessed the T cellresponse to the microbiome (123). The gastrointestinal tractbears the largest microbiome in terms of bacterial number, aswell as in the diversity of species. In the lamina propria of theintestine, up to 30--40% of T cells may be Th17 cells; their pro-duction of IL-17A, IL-17F, and IL-22 contributes to the produc-tion of antimicrobial peptides by intestinal epithelial cells, themaintenance of tight junctions that maintains the barrier func-tion of the epithelium and the secretion of IgA (124, 125).Germ-free mice have limited Th17 cells in the intestine as wellas the skin, confirming the critical role of the microbiome inpromoting Th17 cells (8, 126, 127). One key species involved inthe development of Th17 cells in the gut is SFB (128). The pres-ence of SFB directly correlates with levels of Th17 cells in thegut; however, the initiation of this pathway occurs in the mes-enteric LN (129). Monocyte-derived CX3CR11 cells respond toenvironmental factors driven by SFB to active ILC3s, whichcan promote Th17 cell responses (130). In the mesenteric LN, Tcells upregulate Rorgt, and upon trafficking back to the intesti-nal tissue, they can secrete IL-17 and IL-22 in response to localtissue production of serum amyloid A proteins 1 and 2 (SAA1/2) driven by ILC3 cells (129, 131). Thus, the presence of a singlemicrobe, SFB, is sufficient to promote an environment uniqueto the gut that impacts T cell activation in the local drainingLN. A similar mechanism is operative in the skin, where thecommensal bacteria S. epidermidis is critical for Th17 and IL-17--producing CD8 T cells in the skin (9). Alterations in the gutmicrobiome do not play a role in shaping the T cell response toS. epidermidis, suggesting the local microbiome is shaping thelocal T cell response.

Tregs are also common in the intestine, where they play akey role in maintaining tolerance to the microbiome. Similar toTh17 cells, germ-free mice are largely devoid of intestinalTregs, implicating the microbiome in their induction. TGF-band RA also play a key role in driving Tregs in the gut. Intrigu-ingly, many Tregs in the intestine express Rorgt, suggesting thespecific environment signals of the intestine are optimal forinduction of specific programs in T cells. Specifically, IL-6 andRA in the intestine are key for the induction of Rorgt, inducedvia the presence of a microbiome (132). More recently a role

for diet and microbiome influenced colonic bile acids havebeen shown to induce Rorgt in Tregs, and IL-6 can be pro-duced by enteric nerves in the colonic lamina propria that areheightened in the absence of commensals, leading to anincrease in Rorgt Tregs (133, 134). Alternatively, a Gata31 pop-ulation of Tregs also exists in the intestine that depends on thepresence of IL-33 (135, 136). Unlike SFB, the precise microbialspecies that induce Tregs is less clear. Clostridia strains havebeen shown to induce Tregs in several settings, possibly by theinduction of short-chain fatty acids (SCFA), for which Clos-tridia contain several genes predicted to be capable biosynthesisof SCFA (137). SCFA are natural HDAC inhibitors and thussuppress proinflammatory cytokine production of DCs. Severalother bacterial strains have been linked to Treg induction inthe intestine, and although the precise mechanism of each isstill unclear, the overarching picture is that microbial compo-nents create an environment that is key to generating a tolero-genic state that includes the induction of Tregs and Th17 cells.Importantly, in the setting of systemic inflammation such asviral or parasitic infection, these tolerogenic signals can beoverridden and microbiome-specific T cells converted intoproinflammatory subsets such as Th1 cells (23). Thus, the tissueenvironment is mutable and can be modified to accommodateshifts in the environment to produce the appropriate outputneeded.

In comparison with the intestine or skin, the lung micro-biota is vastly smaller in size; however, there is bacteria presentin the lung that, like the gut and skin, is colonized early in theneonatal period (138). The benefit of the lung microbiome hasbeen primarily studied in the context of allergic asthma, inwhich the presence of a microbiome confers some protectiontoward the development of allergic asthma, likely by drivingTregs, a similar mechanism as the intestine and skin (139--141).The precise nature of this effect is not entirely clear, as depend-ing on the model of allergic asthma used, the level of protectionafforded is different (139, 141). Yet, a collection of studiestogether clearly show that the presence of a lung microbiomedrives Tregs in early life, which is likely to create a tolerogenicenvironment that limits inflammation to allergens (142). Fur-thermore, several lung inflammatory diseases have alteredmicrobiomes, suggesting immune dysregulation leads tochanges in microbial diversity and further suggests the constantrole of the immune system to sense and respond to the micro-biome in the lung (138). It is important to note, however, thatthese spaces are not entirely isolated from one another. Therehas been clear demonstration of a gut--lung axis in bothhumans and mice, as changes in the intestinal microenviron-ment has impacts on lung disease (142--145). Furthermore, theimmune-associated lymphoid tissues of the lung and gut(inducible BALT and GALT) have similarities both in theirfunction and morphology, suggesting cells can migrate betweenthe tissues. Although the precise mechanisms establishing andcontrolling the gut--lung axis remain to be completely defined,the factors shaping one tissue can, in some ways, lead to altera-tions in distant tissues in a coordinated fashion, further




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underscoring the dynamic nature of the immune system withthe changing environment.

Taken together, the interplay of the microbiome with theimmune system at barrier surfaces is undeniable, thus microbialAgs are constantly sampled at each tissue site, helping to shapethe tissue-specific responses that impact downstream adaptiveimmune pathways. Given the requirement of the microbiomefor proper immune tolerance at barrier sites and the dysregula-tion that occurs in the context of inflammatory disease, it isclear that the diversity of the microbiome at the tissues plays akey role in shaping the homeostatic niche found at each site.As the precise bacterial Ags vary by tissue space and potentiallyin response to changes in diet, antibiotic use, etc., the nature ofthe response will be varied as well, thus creating tissue-specifichomeostatic niches that are key to setting the tone of each tis-sue as well as creating the environments in which T cells willbecome activated and differentiate.

Foreign AgsIn addition to tolerance to self-Ags and to microbial Agsdescribed above, the nonpathogenic environmental Ags weencounter daily also require homeostasis. What we eat, whatwe breathe, and what we touch represent many additional for-eign Ags introduced via tissue sites that the immune systemmust recognize and generate homeostasis. And yet, for a sizableportion of the population, tolerance is not intact�inappropriateresponses to nonmicrobial environmental Ags are the primarycause of allergic responses at multiple tissue sites and are onthe rise in both children and adults. Food allergy, skin allergiessuch as atopic dermatitis, and allergic asthma are severalinflammatory responses at tissue sites that play important rolesin morbidity and rising health care costs. In some cases,responses are focused at the primary tissue site of allergeninteraction, for example allergic asthma to inhaled allergens,such as house dust mite. Yet, in most cases, allergies can drivemultitissue responses such as hives or anaphylaxis, particularlyupon secondary encounter. T cell--mediated IgE responses toallergens are thought to largely drive systemic or distal tissueresponses, but initial sensitization of allergens likely occurs in atissue-specific manner. Tolerance mechanisms such as DCs andTregs at the tissue site constantly survey and limit immunereactions to nonpathogenic Ags in a similar manner as micro-bial commensal Ags. Tissue-located DCs constantly sample thelocal Ags and drive Tregs to environmental Ags such as food tolimit any aberrant effector responses that may occur. As eachtissue site experiences different Ags, local environmental diver-sity in Ag exposure likely creates an impression of the tissue inthe draining LN, creating slightly different homeostatic envi-ronments at each LN that may impact immune responses simi-lar to that of the microbiome, as discussed above. In the gut,mechanisms similar to microbial Ag detection are operative:DCs expressing CX3CR1 and CD11b sample luminal contents tocapture Ag (146), whereas direct Ag transfer can occur throughspecialized epithelial cells such as M cells (147). Several factors

play a key role in driving tolerance within the mesenteric LN,such as TGF-b, RA, IDO, and IL-10. Both Tregs and non-Foxp31 Tregs that produce IL-10 maintain tolerance to envi-ronmental Ags, as loss of Tregs will reverse established toler-ance (148). The skin has similar mechanisms, in which aspecialized DC population called LCs as well as dermal DCssample Ag in an immature or tolerogenic state and traffic tothe draining LN to induce T cell responses (149). The skin isalso rich in Trms, which do not circulate, and under homeo-static conditions, many Trms are Tregs or a Tr1 cell that produ-ces IL-10 and TGF-b (150). Largely similar mechanisms exist inthe lung, where Ag is sampled by macrophages and lung DCsand transported to LNs, and drive the production of Tregs, andregulatory tissue-resident memory cells are found in the lungtissue as well. IL-10, TGF-b, and RA are all key players in lungtolerance mechanisms. The circulation of Ag, either carried byDCs or more freely transported, plays a key role in establishingtolerance via induction of Tregs. Therefore, together with themicrobiome, the local environmental Ags encountered at eachtissue site may play a key role in creating tissue-specificresponses both at the tissue site and within the LNs drainingthose tissues, which is likely to play an important role in settingthe environmental tone present when T cells see Ag to becomeactivated and begin their differentiation process.

CONCLUSIONS

The notion of tissue-specific immunity is widely accepted.Each tissue has specific functional needs and is also experienc-ing the surrounding environment based to some extent onthose tissue-specific functions. For example, the mucosal tis-sues such as the lung and gut have specific differences fromthe skin based on its mucosal nature. As such, the immune sys-tem reacts in a tissue-specific manner as well, controlling tol-erance to the environment while also mounting responses toforeign pathogens if needed. These tissue-specific environmen-tal changes impact the immune cells in the tissue directly aswell as those that exist in the draining LN, setting up localneighborhoods in which the LN has tissue-specific featuresthat make it optimally primed to generate a response that isneeded for the tissue in which Ag is encountered. There isample evidence that immune responses to similar Ags havewidely different outcomes depending on the site of Ag intro-duction, and exploration of cells in the tissues and drainingLNs confirm that APCs such as DCs and stromal cells havetranscriptomes consistent with local imprinting from the tis-sue. Furthermore, specific neuron populations at each tissuesite are likely to have an impact on T cell activation and effec-tor function, even if that interaction is indirect. We arguetherefore that these many variables, both intrinsic cellular pop-ulations in the tissue and LN spaces as well as external factorssuch as the metabolism of the tissue or microbiome, can havean important impact on the process of T cell differentiationin vivo. So much of our knowledge on T cell activation and




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effector function in vivo is limited because of technical limita-tions; however, new in vivo and ex vivo assays should allowus to revisit the factors controlling T cell differentiation andfunction to more precisely understand the key tissue-specificfactors that are important for controlling responses to infec-tion through the lens of tissue-specific immunity.

DISCLOSURES

The author has no financial conflicts of interest.

ACKNOWLEDGMENTS

I thank Dr. Timothy Hand, Dr. Dan Kaplan, Dr. Greg Delgoffe, and Dr.Anuradha Ray for discussions related to the ideas in this commentary.

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