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Skin-Resident T Cells: The Ups and Downs of On Site Immunity

  • Rachael A. Clark
    Correspondence
    Department of Dermatology, Brigham and Women's Hospital EBRC Room 505A, 221 Longwood Avenue, Boston, MA, 02115, USA
    Affiliations
    Department of Dermatology, Harvard Skin Disease Research Center, Brigham and Women's Hospital, Boston, Massachusetts, USA
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      The cutaneous surface of a normal adult individual contains approximately 20 billion T cells, nearly twice the number present in the entire circulation. Recent studies have shown a role for these cells in both normal immunity and in inflammatory skin diseases such as psoriasis. Regulatory T cells protect against autoimmune reactions to self antigens and assist in the resolution of cutaneous inflammation. However, they can also shield tumors from immune detection, allow latent infections to persist and can dysfunction under the conditions present in inflammatory skin diseases. Th17 T cells protect organisms against extracellular pathogens but also have a key role in the pathogenesis of psoriasis. Evidence suggests that effector memory T cells produced during immune reactions survive and persist long term within the skin, providing local and rapid protection against pathogen reexposure. This review summarizes the current understanding of how skin-resident T cells contribute to normal and aberrant immunity in the skin.

      Abbreviations

      CLA
      cutaneous lymphocyte antigen
      DC
      dendritic cell
      Tregs
      regulatory T cells
      TCR
      T-cell receptor
      TEM
      effector memory T cell

      Introduction

      T and B lymphocytes rearrange the DNA encoding their antigen receptors and therefore have the capacity to recognize any antigen. These cells also serve as the repositories for immunologic memory; lymphocytes generated during an immune response can persist for decades, providing rapid and specific responses to rechallenge. T and B cells thus provide highly flexible and long-lasting immunity.
      Naive T cells are found primarily within the blood and lymph nodes. Expression of the homing addressins L-selectin and CCR7 supports the migration of naive T cells into lymph nodes where they encounter dendritic cells (DC) bearing antigen derived from the peripheral tissues (
      • Warnock R.A.
      • Askari S.
      • Butcher E.C.
      • von Andrian U.H.
      Molecular mechanisms of lymphocyte homing to peripheral lymph nodes.
      ;
      • Baekkevold E.S.
      • Yamanaka T.
      • Palframan R.T.
      • Carlsen H.S.
      • Reinholt F.P.
      • von Andrian U.H.
      • et al.
      The CCR7 ligand elc (CCL19) is transcytosed in high endothelial venules and mediates T cell recruitment.
      ). When naive T cells encounter their cognate antigen, they differentiate and gain effector functions including cytotoxicity and cytokine production. During this differentiation process, T cells are imprinted to express tissue-specific homing addressins that affect their subsequent migration patterns. In mice, naive transgenic T cells developed expression of the gut homing addressins α4β7 and CCR9 when they first encountered antigen in the gut draining lymph nodes, but expressed the skin homing addressins cutaneous lymphocyte antigen (CLA) and CCR4 if they encountered antigen first in the skin-draining lymph nodes (
      • Campbell J.J.
      • Haraldsen G.
      • Pan J.
      • Rottman J.
      • Qin S.
      • Ponath P.
      • et al.
      The chemokine receptor CCR4 in vascular recognition by cutaneous but not intestinal memory T cells.
      ;
      • Campbell D.J.
      • Butcher E.C.
      Rapid acquisition of tissue-specific homing phenotypes by CD4(+) T cells activated in cutaneous or mucosal lymphoid tissues.
      ). Further studies showed that both DC and lymph node stromal cells have the ability to imprint homing receptor expression on T cells (
      • Mora J.R.
      • Bono M.R.
      • Manjunath N.
      • Weninger W.
      • Cavanagh L.L.
      • Rosemblatt M.
      • et al.
      Selective imprinting of gut-homing T cells by Peyer's patch dendritic cells.
      ,
      • Mora J.R.
      • Cheng G.
      • Picarella D.
      • Briskin M.
      • Buchanan N.
      • von Andrian U.H.
      Reciprocal and dynamic control of CD8 T cell homing by dendritic cells from skin- and gut-associated lymphoid tissues.
      ;
      • Edele F.
      • Molenaar R.
      • Gutle D.
      • Dudda J.C.
      • Jakob T.
      • Homey B.
      • et al.
      Cutting edge: instructive role of peripheral tissue cells in the imprinting of T cell homing receptor patterns.
      ). Effector T cells are thus programmed during differentiation to migrate to the tissue from which their cognate antigen was originally derived.
      When confronted by an infectious pathogen, the immune system does two important things: it responds and it remembers. Two different types of T cells are generated during an immune response (
      • Sallusto F.
      • Lenig D.
      • Forster R.
      • Lipp M.
      • Lanzavecchia A.
      Two subsets of memory T lymphocytes with distinct homing potentials and effector functions.
      ). Effector memory T cells (TEM) upregulate expression of tissue homing addressins and develop effector functions. These cells predominate in the blood in the early stages of an immune response, migrate into peripheral tissues and effect clearance of the pathogen (
      • Mackay C.
      • Marston W.
      • Dudler L.
      Naive and memory T cells show distinct pathways of lymphocyte recirculation.
      ;
      • Whitton J.L.
      • Zhang J.
      Principles of cytotoxic T lymphocyte induction and recognition.
      ). Following the peak of the immune response, most of these cells disappear from the blood and a second population, central memory T cells (TCM) predominates (
      • Razvi E.S.
      • Jiang Z.
      • Woda B.A.
      • Welsh R.M.
      Lymphocyte apoptosis during the silencing of the immune response to acute viral infections in normal, lpr, and Bcl-2-transgenic mice.
      ). Like naive T cells, TCM express the lymph node homing addressins L-selectin and CCR7 and generally lack addressins for peripheral tissues. TCM have lower levels of effector functions but can proliferate vigorously and develop into effector T cells when rechallenged with antigen (
      • Sallusto F.
      • Geginat J.
      • Lanzavecchia A.
      Central memory and effector memory T cell subsets: function, generation, and maintenance.
      ).
      Until fairly recently, it was believed that T cells only entered tissues such as the skin under conditions of active inflammation (
      • Kupper T.S.
      • Fuhlbrigge R.C.
      Immune surveillance in the skin: mechanisms and clinical consequences.
      ). This review will discuss recent findings that skin and other tissues are stably colonized by long-lived populations of memory T cells. These tissue resident T cells provide long lasting, local and rapid responses to pathogen reexposure but can also contribute to inflammatory and autoimmune skin diseases.

      Skin-resident T cells: hiding in plain sight

      It has been known for decades that T cells are present in non-inflamed human skin and it has been proposed that these cells may comprise a skin-specific immune system (
      • Bos J.D.
      • Zonneveld I.
      • Das P.K.
      • Krieg S.R.
      • van der Loos C.M.
      • Kapsenberg M.L.
      The skin immune system (SIS): distribution and immunophenotype of lymphocyte subpopulations in normal human skin.
      ). Comprehensive study of these T cells and an understanding of their true numbers has been difficult because mechanical or enzymatic dissociation of the skin produces very few cells. Despite this difficulty, studies using histologic methods or skin dissociation have successfully showed that >95% of the T cells in normal skin are CD45RO memory T cells, <5% are naive, most express CLA, 50% express CCR8 and a subset express CCR7 and CCR10 (
      • Bos J.D.
      • Hagenaars C.
      • Das P.K.
      • Krieg S.R.
      • Voorn W.J.
      • Kapsenberg M.L.
      Predominance of “memory” T cells (CD4+, CDw29+) over “naïve” T cells (CD4+, CD45R+) in both normal and diseased human skin.
      ;
      • Campbell J.J.
      • Murphy K.E.
      • Kunkel E.J.
      • Brightling C.E.
      • Soler D.
      • Shen Z.
      • et al.
      CCR7 expression and memory T cell diversity in humans.
      ;
      • Homey B.
      • Alenius H.
      • Muller A.
      • Soto H.
      • Bowman E.P.
      • Yuan W.
      • et al.
      CCL27-CCR10 interactions regulate T cell-mediated skin inflammation.
      ;
      • Schaerli P.
      • Ebert L.
      • Willimann K.
      • Blaser A.
      • Roos R.S.
      • Loetscher P.
      • et al.
      A skin-selective homing mechanism for human immune surveillance T cells.
      ).
      T cells are arguably the most migratory cells in the body. T cells enter and travel through every human tissue with the likely exception of cortical bone. Unlike neutrophils and monocyte-derived macrophages, T cell migration into the tissues is not a one-way trip. T cells can migrate into peripheral tissues and then return to the circulation via migration through the lymph nodes. A simple method of isolating skin T cells that took advantage of their tendency to migrate towards chemokines produced by dermal fibroblasts extracted surprising numbers of T cells from normal human skin (
      • Clark R.A.
      • Chong B.F.
      • Mirchandani N.
      • Yamanaka K.
      • Murphy G.F.
      • Dowgiert R.K.
      • et al.
      A novel method for the isolation of skin resident T cells from normal and diseased human skin.
      ). This observation led to the enumeration of T cells in skin and it was found that normal human skin contains about 1 million T cells per cm2 (
      • Clark R.A.
      • Chong B.
      • Mirchandani N.
      • Brinster N.K.
      • Yamanaka K.
      • Dowgiert R.K.
      • et al.
      The vast majority of CLA+ T cells are resident in normal skin.
      ). Extrapolation of this finding suggested that the skin of a normal adult contains approximately 20 billion T cells, nearly twice the number present in the entire blood volume. These T cells coexpressed high levels of the skin homing addressins CLA and CCR4, had a diverse T-cell repertoire and were polarized to produce a variety of different cytokines in response to T-cell stimulation (
      • Clark R.A.
      • Chong B.
      • Mirchandani N.
      • Brinster N.K.
      • Yamanaka K.
      • Dowgiert R.K.
      • et al.
      The vast majority of CLA+ T cells are resident in normal skin.
      ). T cells (80%) in skin lacked expression of CCR7/L-selectin, confirming their identity as effector memory T cells. T cells that did express CCR7 and L-selectin also coexpressed the skin addressins CLA and CCR4, suggesting that they were an intermediate phenotype capable of accessing both the skin and secondary lymphoid organs.
      At the time of these studies, it was assumed that TEM primarily remained in circulation until recruited into the tissues at sites of inflammation. Classical skin homing TEM (CLA+, CCR7/L-selectin) cannot enter the lymph nodes and as a result, should be found either in the blood or the skin. Enumeration of CLA+ T cells in skin and blood showed that >90% of CLA+ skin homing T cells were present in skin under resting, non-inflamed conditions and that less than 10% were in peripheral circulation (
      • Clark R.A.
      • Chong B.
      • Mirchandani N.
      • Brinster N.K.
      • Yamanaka K.
      • Dowgiert R.K.
      • et al.
      The vast majority of CLA+ T cells are resident in normal skin.
      ). Thus, even in the absence of inflammatory stimuli, the vast majority of skin homing TEM were resident in skin and well placed to respond to local challenges.

      Local T-cell responses in skin: lessons from psoriasis

      In considering the treatment of inflammatory skin diseases, we and others have often focused on inhibiting the migration of T cells into skin. E-selectin is expressed by all postcapillary venules in skin and is upregulated with inflammation (
      • Chong B.F.
      • Murphy J.-E.
      • Kupper T.S.
      • Fuhlbrigge R.C.
      E-Selectin, Thymus- and Activation-Regulated Chemokine/CCL17, and Intercellular Adhesion Molecule-1 Are Constitutively Coexpressed in Dermal Microvessels: A Foundation for a Cutaneous Immunosurveillance System.
      ;
      • Kupper T.S.
      • Fuhlbrigge R.C.
      Immune surveillance in the skin: mechanisms and clinical consequences.
      ). By binding to CLA expressed by skin homing T cells, E-selectin supports lymphocyte rolling, the first step of T-cell entry into the skin (
      • Berg E.L.
      • Yoshino T.
      • Rott L.S.
      • Robinson M.K.
      • Warnock R.A.
      • Kishimoto T.K.
      • et al.
      The cutaneous lymphocyte antigen is a skin lymphocyte homing receptor for the vascular lectin endothelial cell-leukocyte adhesion molecule 1.
      ;
      • Kupper T.S.
      • Fuhlbrigge R.C.
      Immune surveillance in the skin: mechanisms and clinical consequences.
      ) . It therefore came as a surprise to find that blockade of E-selectin, which should block migration of T cells into skin, was ineffective in the treatment of psoriasis, a T-cell-mediated inflammatory skin disease (
      • Bhushan M.
      • Bleiker T.O.
      • Ballsdon A.E.
      • Allen M.H.
      • Sopwith M.
      • Robinson M.K.
      • et al.
      Anti-E-selectin is ineffective in the treatment of psoriasis: a randomized trial.
      ).
      This result was made more intelligible by an elegant series of experiments in mice grafted with human psoriatic skin.
      • Boyman O.
      • Hefti H.P.
      • Conrad C.
      • Nickoloff B.J.
      • Suter M.
      • Nestle F.O.
      Spontaneous development of psoriasis in a new animal model shows an essential role for resident T cells and tumor necrosis factor-alpha.
      ) found that normal appearing, non-lesional skin from patients with psoriasis developed full-blown psoriatic lesions when transplanted onto immunodeficient mice but skin taken from normal patients did not. Development of the psoriatic lesion was dependent on the activation and local proliferation of a population of autoreactive T cells transferred with the initial skin graft. These T cells were themselves stimulated into action by the local production of IFN-α by plasmacytoid DC, likely produced in response to the trauma of transplantation (
      • Nestle F.O.
      • Conrad C.
      • Tun-Kyi A.
      • Homey B.
      • Gombert M.
      • Boyman O.
      • et al.
      Plasmacytoid predendritic cells initiate psoriasis through interferon-{alpha} production.
      ).
      This series of experiments showed two important things about skin-resident T cells. First, T cells present in normal appearing skin were able to give rise to a full psoriatic lesion in the absence of T-cell recruitment from blood. Thus, T cells resident in even normal appearing skin can initiate full blown immune responses and although migration of T cells into the skin from the blood occurs in many inflammatory conditions, it may not always be required. In light of these experiments, the failure of E-selectin blockade to control psoriasis became understandable. Autoreactive T cells capable of initiating psoriasis reside within the normal appearing skin of patients with psoriasis. Preventing the entry of additional T cells into skin does not address the threat posed by the lymphocytes already present.
      The second lesson from these experiments is that autoreactive T cells in the skin behave very differently depending on their local inflammatory environment. Autoreactive T cells exist in normal appearing skin from psoriatic patients but these cells remain quiescent despite living side by side with APC expressing and capable of presenting autoantigens. Only when skin APC are activated to produce IFN-α do these autoreactive T cells proliferate, produce cytokines and initiate an active psoriatic lesion. This finding highlights the importance of understanding how T cells are activated by innate immune cells within the skin and explains why TNF antagonists (etanercept, infliximab, adalimumab) and integrin antibodies that disrupt APC/T-cell crosstalk (efalizumab, alefacept) are effective in psoriasis whereas E-selectin blockade is not (
      • Bhushan M.
      • Bleiker T.O.
      • Ballsdon A.E.
      • Allen M.H.
      • Sopwith M.
      • Robinson M.K.
      • et al.
      Anti-E-selectin is ineffective in the treatment of psoriasis: a randomized trial.
      ;
      • Griffiths C.E.
      T-cell-targeted biologicals for psoriasis.
      ).
      Additional studies in mice and humans have confirmed that T cells can become activated, proliferate and carry out effector functions locally within the skin. As is described more fully below, HSV-specific T cells in mice and humans remained localized around latently infected nerves and prevented HSV reactivation (
      • Zhu J.
      • Koelle D.M.
      • Cao J.
      • Vazquez J.
      • Huang M.L.
      • Hladik F.
      • et al.
      Virus-specific CD8+ T cells accumulate near sensory nerve endings in genital skin during subclinical HSV-2 reactivation.
      ;
      • Wakim L.M.
      • Waithman J.
      • van Rooijen N.
      • Heath W.R.
      • Carbone F.R.
      Dendritic cell-induced memory T cell activation in nonlymphoid tissues.
      ). In patients immunized with BCG and challenged with a PPD, effector T cells proliferated within the skin at the PPD site (
      • Vukmanovic-Stejic M.
      • Reed J.R.
      • Lacy K.E.
      • Rustin M.H.
      • Akbar A.N.
      Mantoux Test as a model for a secondary immune response in humans.
      ). In summary, all elements necessary for a memory T-cell response – T cells and APC — are resident within human skin and their interaction can give rise to full secondary immune responses within the skin.

      Regulatory T cells in the skin: the good, the bad and the ineffective

      The immune system is faced with the difficult problem of mounting immune responses to dangerous pathogens while maintaining tolerance to the body's own tissues and to harmless or commensal organisms. Regulatory T cells (Tregs) are one of many mechanisms developed by the immune system to enforce tolerance to harmless and self antigens. Tregs are critical to the development and maintenance of self-tolerance and function by suppressing the activation, cytokine production, and proliferation of other T cells (
      • Sakaguchi S.
      Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self.
      ). These cells are characterized by high expression of the transcription factor FOXP3 and by their ability to suppress T-cell responses in vitro.
      We have found that between 5 and 10% of the T cells resident in normal human skin are FOXP3+ Tregs and that these cells proliferate under conditions similar to those found in inflamed skin (
      • Clark R.A.
      • Kupper T.S.
      IL-15 and dermal fibroblasts induce proliferation of natural regulatory T cells isolated from human skin.
      ;
      • Clark R.A.
      • Huang S.J.
      • Murphy G.F.
      • Mollet I.G.
      • Hijnen D.
      • Muthukuru M.
      • et al.
      Human squamous cell carcinomas evade the immune response by down-regulation of vascular E-selectin and recruitment of regulatory T cells.
      ). This suggests that local proliferation of Tregs in the skin may serve as a brake for cutaneous inflammation. Indeed, Tregs were observed to locally proliferate within human skin during DTH reactions and increased numbers of Tregs were found in the skin lesions of contact dermatitis and resolving fixed drug eruptions (
      • Teraki Y.
      • Shiohara T.
      IFN-gamma-producing effector CD8+ T cells and IL-10-producing regulatory CD4+ T cells in fixed drug eruption.
      ;
      • Vukmanovic-Stejic M.
      • Agius E.
      • Booth N.
      • Dunne P.J.
      • Lacy K.E.
      • Reed J.R.
      • et al.
      The kinetics of CD4+Foxp3+ T cell accumulation during a human cutaneous antigen-specific memory response in vivo.
      ).
      Recent experiments in mice support the idea that Tregs decrease inflammatory tone in the skin. Mice with mutations in FOXP3 lack Tregs and develop widespread and lethal autoimmunity, a condition that can be prevented by the transfer of wild-type Tregs (
      • Khattri R.
      • Cox T.
      • Yasayko S.A.
      • Ramsdell F.
      An essential role for Scurfin in CD4+CD25+ T regulatory cells.
      ). These mice were reconstituted with Tregs that lacked 1,3-fucosyltransferase VII, an enzyme necessary for formation of E-selectin ligands (
      • Malỳ P.
      • Thall A.D.
      • Petryniak B.
      • Rogers C.E.
      • Smith P.L.
      • Marks R.M.
      • et al.
      The [alpha](1,3)Fucosyltransferase Fuc-TVII Controls Leukocyte Trafficking through an Essential Role in L-, E-, and P-selectin Ligand Biosynthesis.
      ). These Tregs functioned normally but had a selective inability to migrate into the skin. These reconstituted mice had decreased inflammation in the liver and lungs, consistent with normal homing of Tregs to these sites, but they had marked skin inflammation. These mice were kept in germ-free facilities and not exposed to pathogens or other inflammatory stimuli, suggesting that the activity of Tregs is needed to control inflammation even in normal, non-challenged skin. These experiments also showed that Tregs need to be present within the skin to exert their anti-inflammatory effects, as opposed to suppressing skin inflammation by acting in the skin draining lymph nodes. This work suggests that Tregs have a role in maintaining homeostasis in normal skin and that they function by locally suppressing the activity of other T cells resident in skin.
      For each mechanism of immune tolerance, there are cancers and pathogens that co-opt it to escape immune detection. Tregs are expanded in patients with many types of cancer and are also often recruited into the tumors themselves (
      • Baecher-Allan C.
      • Anderson D.E.
      Regulatory cells and human cancer.
      ). 50% of the T cells present in human squamous cell carcinomas of the skin are FOXP3+ Tregs and increased Tregs have also been observed in basal cell carcinomas, primary melanoma and melanoma metastases (
      • Kaporis H.G.
      • Guttman-Yassky E.
      • Lowes M.A.
      • Haider A.S.
      • Fuentes-Duculan J.
      • Darabi K.
      • et al.
      Human basal cell carcinoma is associated with Foxp3+ T cells in a Th2 dominant microenvironment.
      ;
      • Mourmouras V.
      • Fimiani M.
      • Rubegni P.
      • Epistolato M.C.
      • Malagnino V.
      • Cardone C.
      • et al.
      Evaluation of tumour-infiltrating CD4+CD25+FOXP3+ regulatory T cells in human cutaneous benign and atypical naevi, melanomas and melanoma metastases.
      ;
      • Ahmadzadeh M.
      • Felipe-Silva A.
      • Heemskerk B.
      • Powell Jr, D.J.
      • Wunderlich J.R.
      • Merino M.J.
      • et al.
      FOXP3 expression accurately defines the population of intratumoral regulatory T cells that selectively accumulate in metastatic melanoma lesions.
      ;
      • Clark R.A.
      • Huang S.J.
      • Murphy G.F.
      • Mollet I.G.
      • Hijnen D.
      • Muthukuru M.
      • et al.
      Human squamous cell carcinomas evade the immune response by down-regulation of vascular E-selectin and recruitment of regulatory T cells.
      ). Topical therapy of human squamous cell carcinomas with imiquimod, a topical immunomodulator and TLR7 agonist, reduced the percentage and suppressive function of Tregs, suggesting that it may be useful in reversing Treg-induced tumor tolerance (
      • Clark R.A.
      • Huang S.J.
      • Murphy G.F.
      • Mollet I.G.
      • Hijnen D.
      • Muthukuru M.
      • et al.
      Human squamous cell carcinomas evade the immune response by down-regulation of vascular E-selectin and recruitment of regulatory T cells.
      ). Tregs also enable latent infection and induce reactivation of cutaneous leishmaniasis and paracoccidiomycosis in mice and likely have a similar role in humans (
      • Belkaid Y.
      • Piccirillo C.A.
      • Mendez S.
      • Shevach E.M.
      • Sacks D.L.
      CD4+CD25+ regulatory T cells control Leishmania major persistence and immunity.
      ;
      • Xu D.
      • Liu H.
      • Komai-Koma M.
      • Campbell C.
      • McSharry C.
      • Alexander J.
      • et al.
      CD4+CD25+ regulatory T cells suppress differentiation and functions of Th1 and Th2 cells, Leishmania major infection, and colitis in mice.
      ).
      Tregs have the capacity to be potently anti-inflammatory but they are ineffective under certain conditions. Tregs can suppress the activity of T cells which have received a low to mid strength T-cell receptor (TCR) signal but cannot suppress T cells that receive a high avidity TCR signal, such as those observed in memory responses to dangerous pathogens (
      • Baecher-Allan C.
      • Viglietta V.
      • Hafler D.A.
      Inhibition of human CD4(+)CD25(+high) regulatory T cell function.
      ). Tregs, therefore, act as the immunologic equivalent of a high band pass filter, suppressing T-cell responses with TCR avidities below a certain threshold and allowing those with higher avidity signals to proceed. Local production of the cytokine IL-6 also renders T cells resistant to the suppressive effects of Tregs in mice and preliminary work suggests this is also true in humans (
      • Goodman W.
      • Massari J.
      • McCormick T.
      • Cooper K.
      Does IL-6 in psoriatic lesions reverse the ability of regulatory T cells to suppress effector T cell proliferation?.
      ;
      • Korn T.
      • Reddy J.
      • Gao W.
      • Bettelli E.
      • Awasthi A.
      • Petersen T.R.
      • et al.
      Myelin-specific regulatory T cells accumulate in the CNS but fail to control autoimmune inflammation.
      ). Expression of the chemokine receptor CCR5 is important for Treg migration and suppressive ability; Tregs that lack CCR5 are less effective in mouse models of paracoccidioidomycosis, leishmaniasis and graft versus host disease (
      • Wysocki C.A.
      • Jiang Q.
      • Panoskaltsis-Mortari A.
      • Taylor P.A.
      • McKinnon K.P.
      • Su L.
      • et al.
      Critical role for CCR5 in the function of donor CD4+CD25+ regulatory T cells during acute graft-versus-host disease.
      ;
      • Yurchenko E.
      • Tritt M.
      • Hay V.
      • Shevach E.M.
      • Belkaid Y.
      • Piccirillo C.A.
      CCR5-dependent homing of naturally occurring CD4+ regulatory T cells to sites of Leishmania major infection favors pathogen persistence.
      ;
      • Moreira A.P.
      • Cavassani K.A.
      • Massafera Tristao F.S.
      • Campanelli A.P.
      • Martinez R.
      • Rossi M.A.
      • et al.
      CCR5-dependent regulatory T cell migration mediates fungal survival and severe immunosuppression.
      ). Lastly, Tregs can be outnumbered. In a mouse model of sarcoma, it was the percentage of Tregs that determined if a tumor would be tolerated or destroyed by the immune system (
      • Bui J.D.
      • Uppaluri R.
      • Hsieh C.S.
      • Schreiber R.D.
      Comparative analysis of regulatory and effector T cells in progressively growing versus rejecting tumors of similar origins.
      ).
      Considerable numbers of Tregs are present in the skin lesions of psoriasis but these cells have decreased suppressive activity (
      • Sugiyama H.
      • Gyulai R.
      • Toichi E.
      • Garaczi E.
      • Shimada S.
      • Stevens S.R.
      • et al.
      Dysfunctional blood and target tissue CD4+CD25high regulatory T cells in psoriasis: mechanism underlying unrestrained pathogenic effector T cell proliferation.
      ). IL-6 is increased in psoriatic skin and this cytokine may interfere with the ability of Tregs to suppress inflammation (
      • Grossman R.M.
      • Krueger J.
      • Yourish D.
      • Granelli-Piperno A.
      • Murphy D.P.
      • May L.T.
      • et al.
      Interleukin 6 is expressed in high levels in psoriatic skin and stimulates proliferation of cultured human keratinocytes.
      ;
      • Goodman W.
      • Massari J.
      • McCormick T.
      • Cooper K.
      Does IL-6 in psoriatic lesions reverse the ability of regulatory T cells to suppress effector T cell proliferation?.
      ) In addition, patients with psoriasis have fewer CCR5+ Tregs than normal individuals and the CCR5+ Tregs that are present in psoriatic patients have decreased function (
      • Sugiyama H.
      • McCormick T.S.
      • Massari J.
      • Shimada S.
      • Cooper K.D.
      CCR5 expressing CD4+CD25high regulatory T cells are both numerically and functionally impaired in patients with psoriasis vulgaris.
      ). Thus it appears that the Tregs present within psoriatic lesions fail to suppress inflammation because they are less active intrinsically and because their activity is antagonized by the pro-inflammatory cytokine milieu in psoriasis.

      Th17 cells in the skin: key players in psoriasis

      Th17 cells are a separate lineage of T cells that produce the Th17 cytokines IL-17A, IL-17F, TNF-α, IL-21 and IL-22 and depend upon IL-23 for their development, survival and proliferation (
      • Harrington L.E.
      • Hatton R.D.
      • Mangan P.R.
      • Turner H.
      • Murphy T.L.
      • Murphy K.M.
      • et al.
      Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages.
      ;
      • Park H.
      • Li Z.
      • Yang X.O.
      • Chang S.H.
      • Nurieva R.
      • Wang Y.H.
      • et al.
      A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17.
      ). Th17 cells provide immunity against a variety of extracellular pathogens, including bacteria such as Klebsiella pneumoniae and fungi such as Cryptococcus neoformans and Candida albicans (
      • Huang W.
      • Na L.
      • Fidel P.L.
      • Schwarzenberger P.
      Requirement of interleukin-17A for systemic anti-Candida albicans host defense in mice.
      ;
      • Happel K.I.
      • Dubin P.J.
      • Zheng M.
      • Ghilardi N.
      • Lockhart C.
      • Quinton L.J.
      • et al.
      Divergent roles of IL-23 and IL-12 in host defense against Klebsiella pneumoniae.
      ;
      • Kleinschek M.A.
      • Muller U.
      • Brodie S.J.
      • Stenzel W.
      • Kohler G.
      • Blumenschein W.M.
      • et al.
      IL-23 enhances the inflammatory cell response in Cryptococcus neoformans infection and induces a cytokine pattern distinct from IL-12.
      ).
      Th17 cells have also been implicated in a variety of inflammatory and autoimmune disorders. IL-17 is increased and Th17 cells are demonstrable in the synovial fluid and tissues of patients with rheumatoid arthritis (
      • Aarvak T.
      • Chabaud M.
      • Miossec P.
      • Natvig J.B.
      IL-17 is produced by some proinflammatory Th1/Th0 cells but not by Th2 cells.
      ;
      • Chabaud M.
      • Durand J.M.
      • Buchs N.
      • Fossiez F.
      • Page G.
      • Frappart L.
      • et al.
      Human interleukin-17: A T cell-derived proinflammatory cytokine produced by the rheumatoid synovium.
      ;
      • Kotake S.
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      • Matsuzaki K.
      • Itoh K.
      • Ishiyama S.
      • et al.
      IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis.
      ) and in the brain lesions and CSF of patients with multiple sclerosis (
      • Matusevicius D.
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      • He B.
      • Kostulas N.
      • Ozenci V.
      • Fredrikson S.
      • et al.
      Interleukin-17 mRNA expression in blood and CSF mononuclear cells is augmented in multiple sclerosis.
      ;
      • Lock C.
      • Hermans G.
      • Pedotti R.
      • Brendolan A.
      • Schadt E.
      • Garren H.
      • et al.
      Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis.
      ). Polymorphisms in the IL-23R, a receptor required for the development and survival of Th17 cells, are associated with susceptibility to ulcerative colitis and Crohn's disease (
      • Duerr R.H.
      • Taylor K.D.
      • Brant S.R.
      • Rioux J.D.
      • Silverberg M.S.
      • Daly M.J.
      • et al.
      A genome-wide association study identifies IL23R as an inflammatory bowel disease gene.
      ). Th17 cells also contribute to the pathology observed in mouse models of colitis, experimental autoimmune encephalomyelitis and arthritis (
      • Ouyang W.
      • Kolls J.K.
      • Zheng Y.
      The Biological Functions of T Helper 17 Cell Effector Cytokines in Inflammation.
      ).
      Increasing evidence suggests that Th17 cells are also key players in the pathogenesis of psoriasis. DC and keratinocytes in the skin lesions of psoriasis produce increased amounts of IL-23, a cytokine that supports the development and proliferation of Th17 cells (
      • Lee E.
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      • Pittman D.
      • Wang F.
      • Chamian F.
      • et al.
      Increased expression of interleukin 23 p19 and p40 in lesional skin of patients with psoriasis vulgaris.
      ;
      • Piskin G.
      • Sylva-Steenland R.M.
      • Bos J.D.
      • Teunissen M.B.
      In vitro and in situ expression of IL-23 by keratinocytes in healthy skin and psoriasis lesions: enhanced expression in psoriatic skin.
      ;
      • Wilson N.J.
      • Boniface K.
      • Chan J.R.
      • McKenzie B.S.
      • Blumenschein W.M.
      • Mattson J.D.
      • et al.
      Development, cytokine profile and function of human interleukin 17-producing helper T cells.
      ;
      • Kryczek I.
      • Bruce A.T.
      • Gudjonsson J.E.
      • Johnston A.
      • Aphale A.
      • Vatan L.
      • et al.
      Induction of IL-17+ T cell trafficking and development by IFN-gamma: mechanism and pathological relevance in psoriasis.
      ;
      • Zaba L.C.
      • Fuentes-Duculan J.
      • Eungdamrong N.J.
      • Abello M.V.
      • Novitskaya I.
      • Pierson K.C.
      • et al.
      Psoriasis Is Characterized by Accumulation of Immunostimulatory and Th1//Th17 Cell-Polarizing Myeloid Dendritic Cells.
      ). Treatment of patients with monoclonal antibodies against IL-12/23p40, a component shared between IL-12 and IL-23, led to significant clinical improvements in psoriasis (
      • Krueger G.G.
      • Langley R.G.
      • Leonardi C.
      • Yeilding N.
      • Guzzo C.
      • Wang Y.
      • et al.
      A human interleukin-12/23 monoclonal antibody for the treatment of psoriasis.
      ;
      • Kimball A.B.
      • Gordon K.B.
      • Langley R.G.
      • Menter A.
      • Chartash E.K.
      • Valdes J.
      Safety and efficacy of ABT-874, a fully human interleukin 12/23 monoclonal antibody, in the treatment of moderate to severe chronic plaque psoriasis: results of a randomized, placebo-controlled, phase 2 trial.
      ). Although this finding could not discriminate between causative roles for IL-23 versus IL-12, a role for IL-23 in psoriasis is supported by genetic studies showing that polymorphisms in the IL-23 receptor and other genes in the IL-23-signaling pathway are associated with psoriasis (
      • Capon F.
      • Di Meglio P.
      • Szaub J.
      • Prescott N.J.
      • Dunster C.
      • Baumber L.
      • et al.
      Sequence variants in the genes for the interleukin-23 receptor (IL23R) and its ligand (IL12B) confer protection against psoriasis.
      ;
      • Cargill M.
      • Schrodi S.J.
      • Chang M.
      • Garcia V.E.
      • Brandon R.
      • Callis K.P.
      • et al.
      A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes.
      ;
      • Nair R.P.
      • Ruether A.
      • Stuart P.E.
      • Jenisch S.
      • Tejasvi T.
      • Hiremagalore R.
      • et al.
      Polymorphisms of the IL12B and IL23R genes are associated with psoriasis.
      ,
      • Nair R.P.
      • Duffin K.C.
      • Helms C.
      • Ding J.
      • Stuart P.E.
      • Goldgar D.
      • et al.
      Genome-wide scan reveals association of psoriasis with IL-23 and NF-[kappa]B pathways.
      ). Th17 cells are demonstrable in psoriatic lesions and are found in higher numbers than in normal human skin (
      • Kryczek I.
      • Bruce A.T.
      • Gudjonsson J.E.
      • Johnston A.
      • Aphale A.
      • Vatan L.
      • et al.
      Induction of IL-17+ T cell trafficking and development by IFN-gamma: mechanism and pathological relevance in psoriasis.
      ;
      • Lowes M.A.
      • Kikuchi T.
      • Fuentes-Duculan J.
      • Cardinale I.
      • Zaba L.C.
      • Haider A.S.
      • et al.
      Psoriasis vulgaris lesions contain discrete populations of Th1 and Th17 T cells.
      ). Th17 cells produce the cytokine IL-22, a cytokine that induces human keratinocyte proliferation and acanthosis in vitro (
      • Sa S.M.
      • Valdez P.A.
      • Wu J.
      • Jung K.
      • Zhong F.
      • Hall L.
      • et al.
      The effects of IL-20 subfamily cytokines on reconstituted human epidermis suggest potential roles in cutaneous innate defense and pathogenic adaptive immunity in psoriasis.
      ). Injection of IL-23 into the skin of mice induced dermal inflammation and epidermal acanthosis reminiscent of the changes seen in psoriasis and these effects were found to be mediated through production of IL-22 (
      • Chan J.R.
      • Blumenschein W.
      • Murphy E.
      • Diveu C.
      • Wiekowski M.
      • Abbondanzo S.
      • et al.
      IL-23 stimulates epidermal hyperplasia via TNF and IL-20R2-dependent mechanisms with implications for psoriasis pathogenesis.
      ;
      • Zheng Y.
      • Danilenko D.M.
      • Valdez P.
      • Kasman I.
      • Eastham-Anderson J.
      • Wu J.
      • et al.
      Interleukin-22, a T(H)17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis.
      ). These findings support a role for IL-23 in supporting the survival, proliferation and function of Th17 T cells that in turn contribute to psoriasis through their production of IL-22 and other inflammatory cytokines. These observations suggest that selective disruption of IL-23 signaling (for example, by targeting IL-23p19 subunit) should lead to reduced Th17 T cells and potentially to long-lasting improvements in psoriasis.

      Tissue resident T cells: on site immune memory

      Central memory T cells (TCM) persist long term in the circulation following resolution of an immune response, a finding that led researchers to propose that TCM are the only T cells responsible for maintaining long-term immunologic memory (
      • Lanzavecchia A.
      • Sallusto F.
      Understanding the generation and function of memory T cell subsets.
      ). This contention is at odds with clear and elegant experiments in mice showing that TEM do persist long term — not in the blood but within the peripheral tissues (
      • Masopust D.
      • Vezys V.
      • Marzo A.L.
      • Lefrancois L.
      Preferential localization of effector memory cells in nonlymphoid tissue.
      ;
      • Reinhardt R.L.
      • Khoruts A.
      • Merica R.
      • Zell T.
      • Jenkins M.K.
      Visualizing the generation of memory CD4 T cells in the whole body.
      ). In animal models, T cells generated during immune responses in the skin, gut, and lungs persist within these tissues and provide protection against reinfection at these sites (
      • Liang S.
      • Mozdzanowska K.
      • Palladino G.
      • Gerhard W.
      Heterosubtypic immunity to influenza type A virus in mice. Effector mechanisms and their longevity.
      ;
      • Hogan R.J.
      • Zhong W.
      • Usherwood E.J.
      • Cookenham T.
      • Roberts A.D.
      • Woodland D.L.
      Protection from respiratory virus infections can be mediated by antigen-specific CD4(+) T cells that persist in the lungs.
      ;
      • Xu R.
      • Johnson A.J.
      • Liggitt D.
      • Bevan M.J.
      Cellular and humoral immunity against vaccinia virus infection of mice.
      ;
      • Stittelaar K.J.
      • van Amerongen G.
      • Kondova I.
      • Kuiken T.
      • van Lavieren R.F.
      • Pistoor F.H.
      • et al.
      Modified vaccinia virus Ankara protects macaques against respiratory challenge with monkeypox virus.
      ). A series of elegant studies examining HSV infection of the skin in mice have provided some intriguing details about the nature of these cells. Following infection with HSV, CD8 antigen-specific T cells accumulated near latently infected dorsal root ganglia and suppressed reactivation of the virus (
      • van Lint A.L.
      • Kleinert L.
      • Clarke S.R.
      • Stock A.
      • Heath W.R.
      • Carbone F.R.
      Latent infection with herpes simplex virus is associated with ongoing CD8+ T-cell stimulation by parenchymal cells within sensory ganglia.
      ;
      • Wakim L.M.
      • Waithman J.
      • van Rooijen N.
      • Heath W.R.
      • Carbone F.R.
      Dendritic cell-induced memory T cell activation in nonlymphoid tissues.
      ). Reinfection with HSV led to local proliferation of these resident cells and also recruitment of additional antigen-specific T cells from the circulation (
      • Wakim L.M.
      • Gebhardt T.
      • Heath W.R.
      • Carbone F.R.
      Cutting edge: local recall responses by memory T cells newly recruited to peripheral nonlymphoid tissues.
      ). There were therefore two populations of antigen-specific T cells capable of responding to rechallenge: skin-resident T cells that arose and were on site as a result of the primary infection and circulating antigen-specific T cells that were newly recruited from the blood. Using GFP-expressing mice and serial transplantation of latently infected ganglia, this group dissected the contributions and characteristics of these two cell types (
      • Gebhardt T.
      • Wakim L.M.
      • Eidsmo L.
      • Reading P.C.
      • Heath W.R.
      • Carbone F.R.
      Memory T cells in nonlymphoid tissue that provide enhanced local immunity during infection with herpes simplex virus.
      ). Surprisingly, antigen-specific tissue resident T cells generated during the primary immune response remained in the same location over 100 days after primary HSV infection. These T cells failed to re-enter the circulation and did not even migrate into infected ganglia transplanted in direct approximation. Antigen-specific T cells were present in highest numbers at the site of initial infection but were also demonstrable in other locations within the skin. These tissue resident T cells provided enhanced local protection against reinfection with HSV. Skin-resident T cells that accumulated after HSV infection lacked L-selectin and expressed higher levels of the activation antigen CD69 than T cells recruited from blood, a finding that has been replicated in humans (
      • Clark R.A.
      • Chong B.
      • Mirchandani N.
      • Brinster N.K.
      • Yamanaka K.
      • Dowgiert R.K.
      • et al.
      The vast majority of CLA+ T cells are resident in normal skin.
      ). These studies showed that a functionally distinct, non-migratory population of skin-resident T cells arose following viral infection, persisted long-term within the skin and provided effective protection against local reinfection. In humans, a similar population of HSV-specific T cells was found resident in the skin of military recruits more than 2 months after clearance of a primary HSV infection and these T cells increased in number during subclinical HSV reactivation (
      • Zhu J.
      • Koelle D.M.
      • Cao J.
      • Vazquez J.
      • Huang M.L.
      • Hladik F.
      • et al.
      Virus-specific CD8+ T cells accumulate near sensory nerve endings in genital skin during subclinical HSV-2 reactivation.
      ). Antigen-specific T cells also persisted long term locally in the skin at the site of PPD injection in BCG-vaccinated individuals (
      • Vukmanovic-Stejic M.
      • Reed J.R.
      • Lacy K.E.
      • Rustin M.H.
      • Akbar A.N.
      Mantoux Test as a model for a secondary immune response in humans.
      ).
      The finding that skin-resident T cells are a sessile, non-migratory population may help to explain some of the puzzling eruptions we see in dermatology. Fixed drug eruptions are local skin lesions that occur following ingestion of a causative drug, spontaneously resolve once the drug is discontinued, then recur in the same location years or even decades later when the drug is taken again. Histologically, this eruption is a cytotoxic reaction against epidermal keratinocytes mediated by a CD8 T cells and indeed, a population of CD8 T cells producing IFN-γ and TNF-α is found within the epidermis of clinically resolved, hyperpigmented fixed drug eruptions lesions (
      • Teraki Y.
      • Moriya N.
      • Shiohara T.
      Drug-induced expression of intercellular adhesion molecule-1 on lesional keratinocytes in fixed drug eruption.
      ;
      • Shiohara T.
      • Moriya N.
      Epidermal T cells: their functional role and disease relevance for dermatologists.
      ;
      • Teraki Y.
      • Shiohara T.
      IFN-gamma-producing effector CD8+ T cells and IL-10-producing regulatory CD4+ T cells in fixed drug eruption.
      ). The fixed location of this eruption may reflect the fixed location of a population of drug reactive T cells resident in skin. Similarly, it is striking how psoriatic plaques remain in the same location long-term and tend to recur in the same locations following cessation of suppressive therapy. Given the evidence that autoreactive Th17 cells may drive this disease, it is tempting to speculate that each psoriatic plaque represents a population of autoreactive skin-resident Th17 cells. However, changes in other cell types could also mediate this localized behavior, including fixed populations of pathogenic APC or possibly fixed changes in the blood vessels at these sites. Lastly, the different behavior of central memory and skin-resident effector memory T cells may underlie the differing clinical manifestations we observe in cutaneous T-cell lymphoma. In patients with stage IA mycosis fungoides, malignant T cells are confined to stable patches and plaques on the skin and life expectancy is normal (
      • Kim Y.H.
      • Liu H.L.
      • Mraz-Gernhard S.
      • Varghese A.
      • Hoppe R.T.
      Long-term outcome of 525 patients with mycosis fungoides and Sezary syndrome: clinical prognostic factors and risk for disease progression.
      ). In Sézary syndrome, the malignant T cells migrate throughout the entire skin surface, giving rise to erythroderma, and also colonize the blood and lymph nodes. Intriguing new data suggest that the malignant T cells in mycosis fungoides are skin-resident effector memory cells, a population expected to remain in a fixed position. However, malignant T cells in Sézary syndrome bear markers suggestive of central memory T cells, a cell type that normally migrates through the blood, lymph nodes, and can also be found in low numbers in normal human skin (
      • Clark R.A.
      • Chong B.
      • Mirchandani N.
      • Brinster N.K.
      • Yamanaka K.
      • Dowgiert R.K.
      • et al.
      The vast majority of CLA+ T cells are resident in normal skin.
      ;
      • Campbell J.J.
      • Soler D.
      • Clark R.A.
      • Kupper T.S.
      Malignant clonal T cells in leukemic (L-)CTCL/Sezary syndrome (SS) exhibit a unique cell surface profile: high and uniform expression of CCR4 and central memory markers CCR7, L-selectin, and CD27.
      ). The fact that malignant central memory T cells give rise to diffuse erythroderma and malignant skin-resident T cells give rise to fixed plaques of inflamed skin is an eloquent argument in favor of the mobile versus sessile nature of these two lymphocyte subsets.
      Other tissues have their own populations of resident T cells that contribute local immune protection. In mice, a population of antigen-specific T cells remained resident in the lung several months after recovery from influenza or Sendai virus infection (
      • Hogan R.J.
      • Usherwood E.J.
      • Zhong W.
      • Roberts A.A.
      • Dutton R.W.
      • Harmsen A.G.
      • et al.
      Activated antigen-specific CD8+ T cells persist in the lungs following recovery from respiratory virus infections.
      ). It was the number of lung resident pathogen-specific T cells and not the number in the lymph nodes that correlated with protection against reinfection. The gut epithelium in mice is colonized by CD8 memory T cells with substantial lytic activity (
      • Masopust D.
      • Vezys V.
      • Marzo A.L.
      • Lefrancois L.
      Preferential localization of effector memory cells in nonlymphoid tissue.
      ). Murine intraepithelial CD8 cells bearing the αβ TCR and both αβ CD8 chains (comparable to conventional T cells) are scarce in the gut at birth but progressively increase throughout life as antigen-experienced T cells accumulate (
      • Cheroutre H.
      Starting at the beginning: new perspectives on the biology of mucosal T cells.
      ;
      • Cheroutre H.
      • Madakamutil L.
      Acquired and natural memory T cells join forces at the mucosal front line.
      ). Gut resident T cells isolated from mice that have recovered from pathogens, such as Toxoplasma gondii protect against infection when transferred into naive animals (
      • Lepage A.C.
      • Buzoni-Gatel D.
      • Bout D.T.
      • Kasper L.H.
      Gut-derived intraepithelial lymphocytes induce long term immunity against Toxoplasma gondii.
      ).

      Central and tissue resident T cells: an integrated view

      To conceptualize how TEM and TCM contribute to immunity, it may be helpful to describe their contributions to both naive and memory T-cell responses in the skin. During a primary immune response, when the immune system encounters an antigen for the first time, the antigen is taken up by skin-resident DC and these cells migrate to the skin-draining lymph nodes (Figure 1). Within the lymph nodes, DC present antigen to naive T cells. Upon recognition of cognate antigen, naive T cells undergo differentiation and polarization into skin homing TEM and TCM. TEM then migrate through the bloodstream and are distributed to all parts of the skin, although the highest numbers of these cells will be found at the site of pathogen exposure (
      • Gebhardt T.
      • Wakim L.M.
      • Eidsmo L.
      • Reading P.C.
      • Heath W.R.
      • Carbone F.R.
      Memory T cells in nonlymphoid tissue that provide enhanced local immunity during infection with herpes simplex virus.
      ). These cells effect clearance of the pathogen and then remain resident locally within the skin (
      • Gebhardt T.
      • Wakim L.M.
      • Eidsmo L.
      • Reading P.C.
      • Heath W.R.
      • Carbone F.R.
      Memory T cells in nonlymphoid tissue that provide enhanced local immunity during infection with herpes simplex virus.
      ). In the early stages of a primary immune response, proliferating T cells are also released from the skin-draining lymph nodes and distribute to antigen-free lymph nodes draining other tissues (
      • Liu L.
      • Fuhlbrigge R.C.
      • Karibian K.
      • Tian T.
      • Kupper T.S.
      Dynamic programming of CD8+ T cell trafficking after live viral immunization.
      ). T cells continue to proliferate within these new lymph nodes and give rise to new populations of effector T cells that migrate to and take up residence in the gut, lungs and other peripheral tissues. In this way, immunization through the skin actually generates widespread systemic immunity via the generation of disparate populations of tissue resident TEM cells.
      Figure thumbnail gr1
      Figure 1Contributions of TEM and TCM to primary immune responses in the skin. After pathogen exposure, DC take up antigen, migrate to the skin draining lymph nodes and present it to naïve T cells. Naïve T cells that recognize their cognate antigen undergo differentiation and polarization into skin homing effector memory T cells (TEM) and central memory T cells (TCM). TEM leave the lymph nodes, enter the circulation and migrate into the skin where they effect clearance of the pathogen. TEM colonize all areas of the skin but are found in highest numbers at sites of pathogen exposure. In the early stages of the immune response, proliferating T cells are also released from the skin draining lymph nodes and migrate to antigen-free lymph nodes draining other peripheral tissues. T cells continue to proliferate within these lymph nodes, giving rise to new populations of TEM that home to gut, lungs and other peripheral tissues. In this way, immunization through the skin gives rise to a diverse population of tissue resident T cells that provide systemic immune protection.
      In a memory immune response, T-cell responses can be divided into three distinct stages (Figure 2). First, local re-exposure to a pathogen leads to antigen uptake and local antigen presentation by tissue-resident DC. These DC stimulate the proliferation and effector functions of antigen-specific skin-resident T cells located in the skin, leading to rapid neutralization of the pathogen (
      • Wakim L.M.
      • Waithman J.
      • van Rooijen N.
      • Heath W.R.
      • Carbone F.R.
      Dendritic cell-induced memory T cell activation in nonlymphoid tissues.
      ). Second, local inflammation leads to upregulation of vascular adhesion receptors on the skin endothelium, leading to nonspecific recruitment of T cells from the circulation. Only a minority of these T cells will be antigen specific, yet the small numbers of antigen-specific cells that do enter the skin under these conditions have been shown to contribute to immune responses (
      • Wakim L.M.
      • Gebhardt T.
      • Heath W.R.
      • Carbone F.R.
      Cutting edge: local recall responses by memory T cells newly recruited to peripheral nonlymphoid tissues.
      ). Third, migration of antigen laden DC to the skin draining lymph nodes will lead to stimulation of TCM and the subsequent production of large numbers of skin-homing TEM. These TEM will then migrate through the bloodstream, enter areas of inflamed skin, and affect clearance of the pathogen.
      Figure thumbnail gr2
      Figure 2The role of TEM and TCM in recall immune responses. Memory immune responses can be divided into three stages. First, DC take up antigen following pathogen re-exposure and present it to TEM resident locally within the skin. These cells proliferate and effect clearance of the pathogen. Second, inflammation leads to endothelial activation and nonspecific recruitment of T cells from the blood. The small numbers of antigen-specific T cells recruited into the skin in this way can also participate in clearance of the pathogen. Third, DC carry endocytosed antigen to the skin draining lymph nodes where it is presented to TCM. These TCM then give rise to new populations of skin homing TEM that migrate to the skin and clear the infection.
      T cells have the flexibility to respond to any antigen, to migrate to any tissue, and to produce a plethora of cytokines and effector functions fine tuned to efficiently eliminate pathogens and tumors. Although tissue-resident T cells have been described in gut, lung and skin, it is likely that all tissue types have to some degree their own populations of resident T cells. By populating both the peripheral tissues and the lymph nodes with distinct types of memory T cells, the adaptive immune system manages to provide both flexibility and the ability to neutralize pathogens rapidly.
      Human skin is populated by 20 billion T cells, charged with the responsibility of locally defending the skin against tumors and pathogens when maintaining tolerance to self antigens exposed during injury. The evolution of this system of local T-cell deposition, combined with amount of energy it takes to generate and maintain these cells, make it clear that defending the skin is a high priority for the immune system. However, skin-resident T cells can dysfunction; these cells can fail to suppress pathogenic inflammation, shield tumors and infections with T cells designed to limit autoimmunity and generate autoreactive T cells that can initiate psoriasis and other inflammatory skin diseases. Studies of the antigen specificity of skin-resident T cells and how they are activated in skin are likely to identify ways that T-cell function can be enhanced in tumors and inhibited in inflammatory skin disorders. Because immune reactions in skin can be visually observed, sampled and manipulated with topical medications, the skin provides an accessible site in which to study human immune responses. Novel therapies arising from an understanding of T biology in skin should be broadly applicable to pathogenic immune states in other tissues.

      Conflict of Interest

      The author states no conflict of interest.

      ACKNOWLEDGMENTS

      In this review, the research described by the author was carried out with the support and advice of Dr Thomas S. Kupper, Chairman of Dermatology at Brigham and Women's Hospital. We thank Adam Calarese and Dr Michael Lichtman for providing helpful suggestions and editorial comments. Our work is supported by NIH Grants 1K08AI060890-01A1, 1R01AR056720-01A1, 1R01CA122569-01A, a Translational Research Award from the Leukemia and Lymphoma Society, a New Investigator Award from the Scleroderma Foundation and a Clinical Investigator Award from the Damon Runyon Cancer Research Foundation.

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