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J Invest Dermatol. Author manuscript; available in PMC 2017 August 10. Published in final edited form as: J Invest Dermatol. 2017 February ; 137(2): 288–294. doi:10.1016/j.jid.2016.08.013.
Emerging Skin T-Cell Functions in Response to Environmental Insults Jutamas Suwanpradid1, Zachary E. Holcomb1,2, and Amanda S. MacLeod1,3,4 1Department 2Duke
of Dermatology, Duke University Medical Center, Durham, North Carolina, USA
University School of Medicine, Durham, North Carolina, USA
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3Department
of Immunology, Duke University Medical Center, Durham, North Carolina, USA
4Pinnell
Center for Investigative Dermatology and Skin Disease Research Center, Duke University Medical Center, Durham, North Carolina, USA
Abstract Skin is the primary barrier between the body and the outside world, functioning not only as a physical barrier, but also as an immunologic first line of defense. A large number of T cells populate the skin. This review highlights the ability of these cutaneous T cells to regulate skinspecific environmental threats, including microbes, injuries, solar UV radiation, and allergens. Since much of this knowledge has been advanced from murine studies, we focus our review on how the mouse state has informed the human state, emphasizing the key parallels and differences.
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INTRODUCTION Mouse models have been instrumental in furthering our understanding of cutaneous T-cell biology and function. Importantly, despite the differences of T-cell types and TCR usage between murine and human skin T cells, many of their roles are shared between these two species. The heterogeneity of cutaneous-resident T cells in murine and human skin is highlighted in Table 1.
T CELLS IN MURINE SKIN
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In a steady state, murine T cells reside predominantly at the epidermal-dermal junction (Figure 1). The epidermis contains a unique population of γδ T cells, called dendritic epidermal T cells (DETCs) (Havran et al., 1989; Tamaki et al., 2001). DETCs reside within the skin near the interface with the skin and the external environment, indicating their role in barrier function and immunity (Girardi et al., 2002, 2006; Jameson et al., 2002; MacLeod et al., 2013; Sharp et al., 2005). DETCs develop in the embryonic thymus and express an invariant VΓ3Vδ1TCR, yet the antigen of the DETC remains elusive. In addition, DETCs
Correspondence: Amanda S. (Büchau) MacLeod, Laboratory for Cutaneous Immunobiology, Department of Dermatology, Duke University Medical Center, Purple Zone, DUMC 3135, 40 Duke Medicine Circle, Durham, North Carolina 27710, USA. [email protected]. CONFLICT OF INTEREST The authors state no conflict of interest.
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also express natural killer group receptor 2D (NKG2D) and can receive signals from NKG2D ligands, expressed by stressed keratinocytes (Nielsen et al., 2015; Strid et al., 2008). In a steady state, DETCs form polarized immunologic synapses that anchor to keratinocyte tight junctions and likely provide TCR-mediated signals for maintenance in the skin (Chodaczek et al., 2012). Despite detailed experimental analyses, a DETC population has not been identified in human skin. The dermis of healthy mice contains both Γδ and αβ T cells. Murine dermal Γδ T cells are self-renewing and are largely maintained independently of circulating precursors (Sumaria et al., 2011). Similar to DETCs, dermal Γδ T cells display an activated memory-like CD44+CD69+CD103+ phenotype;however, they express variant Γδ TCR chains, with some preference for VΓ4 (Sumaria et al., 2011). DETCs require TCR (co-)stimulation, dermal Γδ T cells are highly “innate” and sensitive to cytokine and pathogen-associated molecular pattern recognition (MacLeod et al., 2013; Nielsen et al., 2014, 2015; Strid et al., 2008; Witherden et al., 2010, 2012). Whereas DETCs are dependent on both IL-7 and IL-15 for survival and maintenance, Vγ4+ dermal γδ T cells are largely dependent on IL-7 but not IL-15. A small subset of VΓ4+ dermal Γδ T cells is IL-7 independent (Sumaria et al., 2011; Ye et al., 2001).
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Under homeostatic conditions, αβ TCR+ T cells comprise approximately 40–50% of all dermal T cells (Cai et al., 2011; Sumaria et al., 2011). Both CD8+ and CD4+ T cells, the latter comprising regulatory T cells (TREG) and nonregulatory T cells, exhibit strong tropism for the hair follicle region (Figure 1), suggesting that the hair follicle is critical in regulating skin residence of these tissue-resident memory T cells (TRM) (Chow et al., 2013; Collins et al., 2016; Gratz et al., 2013). Studies demonstrate that hair follicle epithelial cells produce IL-7 and IL-15, the former cytokine required for both CD4+ and CD8+ TRM persistence, whereas the latter is required for CD8+ TRM epidermotropism (Adachi et al., 2015; Gratz et al., 2013; Lawson et al., 2015). Epidermal TRM are comprised predominantly of CD8+ T cells, and similar to DETCs, these cells typically bear the α-chain of the integrin αEβ7 and CD103, and express the activation marker CD69 (Adachi et al., 2015; Mackay et al., 2013). CD103-mediated retention of T cells in the skin likely occurs via adhesion to E-cadherin. Integrins expressed by the interfollicular and isthmus keratinocytes of the hair follicle activate latent transforming growth factor-β production in the skin, which enhances CD103 expression (Adachi et al., 2015; Casey et al., 2012; El-Asady et al., 2005; Mackay et al., 2013; Masopust et al., 2010; Mohammed et al., 2016).
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The murine skin also contains CD103−CD8+ TRM cells (Mackay et al., 2013), but the underlying mechanisms of their maintenance in the skin are not well understood. CD69 suppresses sphingosine-1-phosphate receptor 1, a molecule known to prevent T cells from emigrating from lymphoid organs or other tissues into the skin (Skon et al., 2013). Furthermore, CCR4 and CD103 expressed by dermal TREG cells are critical to TREG migratory behavior and maintenance in the skin, respectively (Chow et al., 2013; Suffia et al., 2005). Disruption of the skin barrier induces αβ T-cell migration to and from the lymph node, including effector TEFF, regulatory, and central memory T cells (TCM) (Bromley et al., 2013; Mackay et al., 2013; Tomura et al., 2010), and many of them become long-lived antigen-specific skin-resident memory T cells, termed TRM. The critical roles of αβ and γδ T cells in the contexts of defense against skin infections, host-microbiome interactions, and skin damage will be discussed in this review article. J Invest Dermatol. Author manuscript; available in PMC 2017 August 10.
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THE CUTANEOUS T-CELL REPERTOIRE IN HUMAN SKIN
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Both epidermal and dermal γδ and αβ T cells are present in noninflamed human skin;however, cutaneous γδ T cells are approximately 300 times less abundant than αβ T cells (Clark et al., 2006; Streilein, 1983; Toulon et al., 2009; Watanabe et al., 2015). Cutaneous γδ T cells express predominantly the Vδ1 TCR chain and the skin-homing cutaneous lymphocyte antigen (CLA) (Toulon et al., 2009). TRM participate in immunosurveillance because of their robust and long-lasting memory responses and derive from a surviving effector T cells (TEFF) pool. Human skin TRM comprise CD103+ and CD103− subsets;CD103+ T cells are enriched in the epidermis, whereas CD103− TRM are more frequent in the dermis (Watanabe et al., 2015). Recent studies demonstrate that in addition to TRM, there are two subsets of CCR7+ TCM that can also migrate to the skin. One subset coexpresses L-selectin (CD62L), whereas the other subset does not;the latter subset has been termed migratory memory T cells (Park and Kupper, 2015). In addition, healthy human skin also harbors Foxp3+ memory regulatory T cells, termed mTREG cells, residing around hair follicles where they contribute to immune homeostasis, or if dysregulated can mediate immunopathology (Chow et al., 2013; Sanchez Rodriguez et al., 2014; Seneschal et al., 2012). The composition and function of cutaneous T cells can change dramatically on environmental insults and may be driven by both antigen exposure and innate immune signals derived from surrounding keratinocytes, dendritic cells, macrophages, and other cells (Iwasaki and Medzhitov, 2015; Schroder et al., 2006). This review article focuses on the effects of cutaneous T-cell activation in the context of environmental insults and the factors that maintain T cells in the skin to provide long-lived protective functions.
CONTROL OF COMMENSAL AND PATHOGENIC MICROBIOTA BY SKIN T Author Manuscript
CELLS
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The cutaneous microbiome is highly diverse and consists of trillions of bacteria, fungi, viruses, archaea, and small arthropods (Byrd and Segre, 2015; Costello et al., 2009; Grice et al., 2009; Human Microbiome Project Consortium, 2012; Kong and Segre, 2012). The composition of the mouse and human skin microbiome differs extensively in both species, but the microbiome exists without generating a host immunologic response. This concept of host-microbiome tolerance in the skin is supported by a recent study in mice showing that pathogen-specific Foxp3-expressing TREG populate the skin postnatally, at a time where commensal colonization of the skin occurs (Scharschmidt et al., 2015). In contrast, dysbiosis is associated with multiple skin diseases, including atopic eczema, and is associated with dysregulated T-cell function (Kobayashi et al., 2015). In humans, commensal microorganisms inhabit the stratum corneum and hair follicle, and possibly even the deeper dermis (Nakatsuji et al., 2013). Changes in the microbiome occur both physiologically and in the setting of skin disease (Kong et al., 2012; Zeeuwen et al., 2012). Based on recent studies, on one hand, the microbiome can enhance protective immunity against pathogens may be driven by cutaneous T cells (and may include additional immune cells). On the other hand, microbiota fine-tune cutaneous T-cell immunity (Naik et al., 2012). Whether the cutaneous microbiome is regulated by antimicrobial peptides and proteins that are inducible by skin T-cell-derived cytokines, including IL-22 and IL-17A, is of particular interest
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(Eyerich et al., 2009; MacLeod et al., 2013; Naik et al., 2012; Sonnenberg et al., 2011). Furthermore, given the recent discovery of a lipid-reactive and CD1a-restricted skin-homing T-cell population producing high levels of IL-22 (de Jong et al., 2014), future studies to determine whether skin lipids derived from microbiota can directly regulate T-cell homing and maintenance in human skin are needed. Elucidating in detail the functional interactions between microbiome diversity and skin T cells in a steady state and in several skin diseases will provide novel strategies for therapies.
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Multiple mouse models have advanced our understanding of cutaneous protective TRM functions in the context of viral infections, including cutaneous herpes simplex virus (HSV)-1 and vaccinia virus infections. Here, TRM cells reside in the skin during the effector phase of the immune response and persist for several months to provide optimal protection against reinfection by the generation of high levels of IFN-γ. CD8+ TRM primarily accumulate in the epidermis, whereas CD4+ TRM primarily accumulate within the upper dermis (Collins et al., 2016; Gaide et al., 2015; Gebhardt et al., 2009, 2011; Heath and Carbone, 2013; Jiang et al., 2012; Mackay et al., 2012). Keratinocytes are the target cells of most cutaneous viruses; thus, epidermal CD8+ TRM may provide superior protection against viral infections (Mackay et al., 2012; Wakim et al., 2008; Zaid et al., 2014). Epidermal CD8+ TRM residence involves a concomitant local reduction in DETC numbers in the epidermis, indicating that these populations persist in mutual exclusion and may compete for local survival signals (Zaid et al., 2014). Upon viral infection, clusters of IFN-γ-producing CD4+ T cells surrounding hair follicles appear and contain CCL5-producing (APCS), as well CD8+ T cells that increase CD4+ T-cell recruitment into the skin (Collins et al., 2016).
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In contrast to viral infections, immune surveillance against cutaneous bacterial and fungal infections is largely provided by γδ T cells. Here, cutaneous IL-17-producing γδ T cells are critical to combat murine cutaneous Staphylococcus aureus and Candida albicans infections (Cho et al., 2010; Kashem et al., 2015). However, whether previous infections and induction of IL-17-producing T cells lead to generation of long-term “γδ–TRM” and at least partial protection against reinfection is currently unknown.
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The functional roles of TRM in human skin in the context of pathogenic infections have been enhanced by ex vivo and in vitro studies, but they are largely correlative in nature. Human skin from newborns, but not from adults, harbors effector T cells that produce high levels of IL-8 (CXCL8) to activate antimicrobial neutrophils and γδ T cells (Gibbons et al., 2014). Adult CLA+ skin-tropic T cells proliferate strongly in vitro after stimulation with pathogens commonly encountered at the cutaneous epithelial surface, such as S. epidermidis, the herpes simplex virus (HSV)-1, and Candida. Notably, in response to C. albicans stimulation, skin-homing T cells isolated from human blood produce IL-9 to enhance effector function of IL-9-producing T helper type 9 (Th9) cells and other effector T cells. Moreover, these Th9 cells reside in healthy human skin and comprise a small but distinct TRM subset (Schlapbach et al., 2014). Furthermore, staphylococcal exotoxins trigger IL-22 production from skinhoming Th22, indicating their potential role in host defense and triggering skin inflammation (Kobayashi et al., 2015; Niebuhr et al., 2010).
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SKIN T CELLS PROMOTE WOUND HEALING AND RE-ESTABLISH THE ANTIMICROBIAL BARRIER
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Upon skin injury, inflammatory and antimicrobial immune responses are aimed at rapidly clearing microbial contamination before an anti-inflammatory repair program can facilitate wound closure. In mice, γδ T cells, in particular DETCs, have been shown to play critical roles in skin wound repair through recognizing a stress-induced DETC antigen on damaged keratinocytes (Komori et al., 2012), and subsequently stimulating the re-establishment of the skin antimicrobial and physical barrier (Jameson et al., 2002; MacLeod et al., 2013). Whether the previously suggested DETC antigen, Skint-1, truly mediates the stress-induced DETC activation upon wounding needs additional proof, as Skint-1 has not been successfully visualized in the skin nor in the thymus (Barbee et al., 2011). Once activated, a subset of DETCs rapidly produces IL-17A upon skin injury, before the influx of additional peripheral T cells into the skin (Baum and Arpey, 2005; MacLeod et al., 2013), and induces epidermal host-defense molecules, including β-defensin 3, S100A8, and RegIIIg (MacLeod et al., 2013). These antimicrobial peptides and proteins function not only by killing microbes, but also by regulating keratinocyte migration, energy metabolism, cytoskeletal dynamics, and keratinocyte proliferation and differentiation in the skin (Lai et al., 2012; MacLeod et al., 2013; Thorey et al., 2001). Additional cytokines and keratinocyte growth factor are produced by skin-resident γδ T cells in mice to stimulate keratinocyte proliferation (Barbee et al., 2011). Cutaneous TREG cells regulate the transition from wound inflammation to the anti-inflammatory repair phase, as these cells promote wound repair through controlling overt inflammation and proinflammatory macrophage accumulation in murine skin wounds (Nosbaum et al., 2016).
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Human cutaneous αβ and γδ T cells play pivotal roles in wound repair as well. An elegant study by Toulon et al. (2009) demonstrated that αβ and γδ TCR+ skin-resident T cells isolated from acute, but not from nonhealing chronic wounds, produce insulin-like growth factor 1 upon activation to promote wound repair. Furthermore, human cutaneous T helper type 22 cells produce IL-22, IL-17, and other cytokines. They can stimulate keratinocyte production of antimicrobial peptides and proteins and directly induce keratinocyte proliferation, and collagen and fibronectin production (Eyerich et al., 2009; Lai et al., 2012; McGee et al., 2013). Whether TREG cells also control cutaneous wound repair in humans has not been fully elucidated.
SKIN T CELLS AND UV RADIATION Author Manuscript
Solar UV radiation is a major environmental stressor causing skin damage. The major events studied in the skin after UV exposure are induction of DNA damage, inflammation, immunosuppression, and carcinogenesis. The role of skin T cells in UV-irradiated skin is thus very complex and will be summarized here. UV radiation induces DNA damage through creation of photoproducts and reactive oxygen species, either through direct induction of chemical reactions within DNA or through DNAstrand breaks (Barnes et al., 2010; Gehrke et al., 2013; Greinert et al., 2012; Kripke et al., 1992; Lankinen et al., 1996). UVB radiation (290–320 nm wavelength) and wavelengths
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close to the UVB spectrum are particularly associated with DNA damage and carry a high risk of inducing genetic instability and cancer (Rünger, 2013). In vivo mouse studies focusing on responses to acute inflammatory UV-induced DNA damage have identified critical functions of DETCs in epidermal DNA damage repair (MacLeod et al., 2014). Mechanistically, UV-irradiated damaged keratinocytes release ATP, which is sensed by purinergic receptors on DETCs and other skin cells, leading to increased DETC IL-17A production. IL-17A induces an epidermal tumor necrosis factor-related weak inducer of apoptosis and growth arrest, and DNA damage-associated gene 45, these two molecules are linked to the DNA repair response and regulation of cell survival and cell death (Hildesheim et al., 2002; MacLeod et al., 2014; Sabour Alaoui et al., 2012). Although this study suggests that DETCs can reduce keratinocyte DNA damage, by limiting γH2AX and cyclobutane pyrimidine dimers, early on, a recent study by Girardi’s group reported that once UVinduced p53 mutations in keratinocytes are acquired, T cells may not be critical in controlling Langerhans cell-driven expansion of these p53 mutant clones (Lewis et al., 2015). However, given the protective cytotoxic role of effector and memory T cells in cancer immunosurveillance (Girardi et al., 2001; Nasti et al., 2011; Strid et al., 2008) and the induction of TREG cells by UV-associated with immunosuppression (Schwarz et al., 2011), it remains to be determined which roles αβ versus γδ T cells play at distinct stages of skin cancer initiation, promotion, and progression.
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UV radiation has dramatic tolerogenic and immunosuppressive effects on T cells, both locally and systemically. Elegant studies performed in mice have shown that UV-induced tolerance involves the suppression of cutaneous CD4+ and CD8+ effector functions, and this increases TREG activity in the context of allergic contact hypersensitivity and transplantable tumor models (Rana et al., 2008; Schwarz et al., 2005, 2011; Toichi et al., 2002). Together, these studies indicate that maintaining genome integrity in the setting of UV-induced DNA damage, as well as additional immune-protective cytotoxic T-cell functions, is vital for the prevention of early tumor initiation and these protective responses are likely suppressed during skin carcinogenesis (Girardi et al., 2001; MacLeod et al., 2014).
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Human cutaneous T-cell responses to acute and chronic UV radiation show some parallels to those observed in mice. Both tumor necrosis factor-related weak inducer of apoptosis and growth arrest and DNA damage-associated gene 45 playa role in human skin homeostasis (Maeda et al., 2003; Sabour Alaoui et al., 2012) and are induced by T-cell-derived IL-17A (MacLeod et al., 2014). IL-17A generation is stimulated from human cutaneous TRM by extracellular ATP, a danger signal released upon UV damage (MacLeod et al., 2014). However, future studies will need to clarify in detail the role of human T cells in keratinocyte DNA damage response and how these processes are suppressed in UV-induced skin cancers, such as squamous cell carcinomas and basal cell carcinomas. Similar to mice, UV exposure sufficiently suppresses T-cell-mediated elicitation reactions of contact hypersensitivity responses in human skin (Cooper et al., 1992; Kelly et al., 1998), indicating that there are strong tolerogenic effects of UV on cutaneous TRM. These effects may directly contribute to the development of human squamous cell carcinomas, which are characterized by numeric and qualitative changes of TRM in the skin with increased frequency of TREG cells (Clark et al., 2008; McCray et al., 2015). Because TRM differ between humans and mice (see Table 1), determining which subsets of human cutaneous T cells distinctly J Invest Dermatol. Author manuscript; available in PMC 2017 August 10.
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contribute to skin cancer suppression and promotion, and identification of the molecular mechanisms will allow novel targeted therapies.
PATHOLOGIC ROLES FOR SKIN T CELLS IN HYPERSENSITIVITY REACTIONS TO CONTACT ALLERGEN AND DRUGS
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Environmental contact allergens such as nickel, perfumes, latex, and poison ivy, can result in T-cell-driven skin inflammation, commonly known as allergic contact dermatitis. Murine delayed contact hypersensitivity (CHS) is an experimental model of human allergic contact dermatitis and consists of two separate phases: sensitization and elicitation (He et al., 2009; Heo et al., 2015; Wang et al., 2000; Xu et al., 1996). The initial sensitization phase is characterized by the formation of complexes between allergens and epidermal proteins, which are subsequently taken up and presented by APCs. These APCs migrate to the draining lymph nodes to present these complexes to naïve T cells, leading them to differentiate into TCM and TRM. These TCM and TRM cells have overlapping TCR repertoires (Gaide et al., 2015) and serve as the major effector cells for mediating the robust inflammatory damaging response in the elicitation phase of CHS. Notably, despite identical TCRs, TRM have a stronger and more rapid response than TCM after re-exposure to the same contact allergen (Gaide et al., 2015). Whether this is simply the result of distinct anatomic locations is currently unknown. In addition to αβ T cells, γδ T cells also play important roles in the murine CHS response. Upon contact allergen exposure, keratinocyte-derived IL-1β triggers IL-17A production in DETCs to mediate inflammation (Nielsen et al., 2014). In contrast, TREG cells serve an immunosuppressive function and negatively regulate the CHS responses via the suppression of T-cell effector functions (Christensen et al., 2015; Gomez de Aguero et al., 2012; Honda et al., 2010). Whether langerin-expressing Langerhans cells, the enigmatic dendritic cell population within the epidermis, or langerin+ dermal dendritic cells activate TREG and play suppressive roles in CHS, or are relevant as APCs at the sensitization phase, remains a matter of debate. Differences and paradoxical findings, however, may be due to differences in allergen applications and/or the timing of ablation of langerin+ cells via diphtheria toxin in the CHS model using langerin-diphtheria toxin receptor (DTR) mice (Bennet et al., 2005, 2007; Gomez de Aguero et al., 2012; Honda et al., 2010; Kaplan et al., 2005; Kissenpfennig et al., 2005).
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In human skin, CD4+ Th1 and Th2 subsets, along with CD8+ T cells, serve as effector cells in allergic contact dermatitis (Cavani et al., 2001);however, the role of γδ T cells in allergic contact dermatitis in humans is still poorly understood. Notably, cutaneous T cells mediate damage to epidermal keratinocytes, a phenomenon also observed in fixed drug eruptions (FDEs). FDEs are skin lesions occurring after repeated ingestion of causative drugs, and similar to a contact allergy, FDE resembles a cytotoxic reaction of cutaneous CD8+ T cells against epidermal keratinocytes in human skin. Of note, new FDE lesions often develop at the site of a previous viral infection, suggesting that protective antiviral long-lived CD8+ TRM cells in the skin may be reactivated by antigen cross-presentation to subsequently induce FDE lesions. However, FDE cannot be considered a true delayed type IV allergy response such as allergic contact dermatitis, and is instead characterized by the “conversion”
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of lesional CD8+CD45RO+ TRM into CD8+CD45Ra+ T cells in clinically resolved skin (Shiohara et al., 2015).
CONCLUSIONS
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Functional studies in mice and humans have highlighted the relevance of T cells in cutaneous immunology and maintenance of the body’s first line of defense. Cutaneous memory T cells play pivotal effector roles as “gate keepers” against environmental insults through regulation and protection against microbes, injury, and cancer development. TREG are critical in maintaining immune tolerance against self-antigens and promoting skin repair. Dysregulation and overly vigorous activation of skin T cells can cause detrimental effects, resulting in skin pathology. The heterogeneity of skin T cells is just beginning to be understood, and future studies are required to further define skin T-cell subsets and their anatomical, structural, and functional relationships. Novel therapeutic strategies to either inhibit or augment skin T-cell function are being developed for clinical use, and specific targeting of these cells holds promise for the treatment of a variety of human skin conditions, including autoimmune diseases, infections, and cancer.
Acknowledgments We apologize to all authors whose work could not be cited here due to space limitations. ASM is supported by the NIH through award K08AR063729 05. As a Duke Cancer Institute member, we gratefully acknowledge grantsupport from the Duke Cancer Institute (to ASM) as part of the P30 Cancer Center Support Grant (P30CA014236). As a member of the Skin Disease Research Center and Pinnell Center for Investigative Dermatology, we gratefully acknowledge grant support (to ASM) from the Duke Skin Disease Research Center (P30AR066527 02) and Pinnell Center for Investigative Dermatology and Skin Disease Research Center at Duke University Medical Center.
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Abbreviations
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APC
antigen-presenting cell
CHS
contact hypersensitivity
CLA
cutaneous lymphocyte-associated antigen
DETC
dendritic epidermal T cell
FDE
fixed drug eruption
TCM
central memory T cell
TEFF
effector T cell
Th
T helper
TREG
regulatory T cell
TRM
tissue-resident memory T cell
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Figure 1. Murine and human skin harbors T cells
The illustration of diverse cutaneous T cell populations in the human and mouse. DETC, dendritic epidermal T cell; TRM, tissue-resident memory T cell.
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Table 1
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Heterogeneity of human and murine skin resident T cells Location
T-cell subset
Mouse
Epidermis
γδ T cells
Epidermis
CD4+ T cell
CD103+ > CD103− TRM
CD103+ > CD103− TRM
Epidermis
CD4+ TREG
FoxP3+ TREG
FoxP3+ TREG
Epidermis
CD8+ T cell
CD103+ > CD103− TRM
CD103+ > CD103− TRM
Dermis
γδ T cells
Vγ4−/+
Vδ1+ enriched
Dermis
CD4+ T cell
FoxP3− TRM
CD103− > CD103+ TRM
Dermis
CD4+ TREG
FoxP3+ mTREG
FoxP3+ TREG
Dermis
CD8+ T cell
CD103− > CD103+ TRM
CD103− > CD103+ TRM
DETC
(Vγ3+Vδ1+)
Human Vδ1+ enriched
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Abbreviations: DETC, dendritic epidermal T cell; TREG, regulatory T cell; TRM, tissue-resident memory T cell.
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J Invest Dermatol. Author manuscript; available in PMC 2017 August 10. Published in final edited form as: J Invest Dermatol. 2017 February ; 137(2): 288–294. doi:10.1016/j.jid.2016.08.013.
Emerging Skin T-Cell Functions in Response to Environmental Insults Jutamas Suwanpradid1, Zachary E. Holcomb1,2, and Amanda S. MacLeod1,3,4 1Department 2Duke
of Dermatology, Duke University Medical Center, Durham, North Carolina, USA
University School of Medicine, Durham, North Carolina, USA
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3Department
of Immunology, Duke University Medical Center, Durham, North Carolina, USA
4Pinnell
Center for Investigative Dermatology and Skin Disease Research Center, Duke University Medical Center, Durham, North Carolina, USA
Abstract Skin is the primary barrier between the body and the outside world, functioning not only as a physical barrier, but also as an immunologic first line of defense. A large number of T cells populate the skin. This review highlights the ability of these cutaneous T cells to regulate skinspecific environmental threats, including microbes, injuries, solar UV radiation, and allergens. Since much of this knowledge has been advanced from murine studies, we focus our review on how the mouse state has informed the human state, emphasizing the key parallels and differences.
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INTRODUCTION Mouse models have been instrumental in furthering our understanding of cutaneous T-cell biology and function. Importantly, despite the differences of T-cell types and TCR usage between murine and human skin T cells, many of their roles are shared between these two species. The heterogeneity of cutaneous-resident T cells in murine and human skin is highlighted in Table 1.
T CELLS IN MURINE SKIN
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In a steady state, murine T cells reside predominantly at the epidermal-dermal junction (Figure 1). The epidermis contains a unique population of γδ T cells, called dendritic epidermal T cells (DETCs) (Havran et al., 1989; Tamaki et al., 2001). DETCs reside within the skin near the interface with the skin and the external environment, indicating their role in barrier function and immunity (Girardi et al., 2002, 2006; Jameson et al., 2002; MacLeod et al., 2013; Sharp et al., 2005). DETCs develop in the embryonic thymus and express an invariant VΓ3Vδ1TCR, yet the antigen of the DETC remains elusive. In addition, DETCs
Correspondence: Amanda S. (Büchau) MacLeod, Laboratory for Cutaneous Immunobiology, Department of Dermatology, Duke University Medical Center, Purple Zone, DUMC 3135, 40 Duke Medicine Circle, Durham, North Carolina 27710, USA. [email protected]. CONFLICT OF INTEREST The authors state no conflict of interest.
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also express natural killer group receptor 2D (NKG2D) and can receive signals from NKG2D ligands, expressed by stressed keratinocytes (Nielsen et al., 2015; Strid et al., 2008). In a steady state, DETCs form polarized immunologic synapses that anchor to keratinocyte tight junctions and likely provide TCR-mediated signals for maintenance in the skin (Chodaczek et al., 2012). Despite detailed experimental analyses, a DETC population has not been identified in human skin. The dermis of healthy mice contains both Γδ and αβ T cells. Murine dermal Γδ T cells are self-renewing and are largely maintained independently of circulating precursors (Sumaria et al., 2011). Similar to DETCs, dermal Γδ T cells display an activated memory-like CD44+CD69+CD103+ phenotype;however, they express variant Γδ TCR chains, with some preference for VΓ4 (Sumaria et al., 2011). DETCs require TCR (co-)stimulation, dermal Γδ T cells are highly “innate” and sensitive to cytokine and pathogen-associated molecular pattern recognition (MacLeod et al., 2013; Nielsen et al., 2014, 2015; Strid et al., 2008; Witherden et al., 2010, 2012). Whereas DETCs are dependent on both IL-7 and IL-15 for survival and maintenance, Vγ4+ dermal γδ T cells are largely dependent on IL-7 but not IL-15. A small subset of VΓ4+ dermal Γδ T cells is IL-7 independent (Sumaria et al., 2011; Ye et al., 2001).
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Under homeostatic conditions, αβ TCR+ T cells comprise approximately 40–50% of all dermal T cells (Cai et al., 2011; Sumaria et al., 2011). Both CD8+ and CD4+ T cells, the latter comprising regulatory T cells (TREG) and nonregulatory T cells, exhibit strong tropism for the hair follicle region (Figure 1), suggesting that the hair follicle is critical in regulating skin residence of these tissue-resident memory T cells (TRM) (Chow et al., 2013; Collins et al., 2016; Gratz et al., 2013). Studies demonstrate that hair follicle epithelial cells produce IL-7 and IL-15, the former cytokine required for both CD4+ and CD8+ TRM persistence, whereas the latter is required for CD8+ TRM epidermotropism (Adachi et al., 2015; Gratz et al., 2013; Lawson et al., 2015). Epidermal TRM are comprised predominantly of CD8+ T cells, and similar to DETCs, these cells typically bear the α-chain of the integrin αEβ7 and CD103, and express the activation marker CD69 (Adachi et al., 2015; Mackay et al., 2013). CD103-mediated retention of T cells in the skin likely occurs via adhesion to E-cadherin. Integrins expressed by the interfollicular and isthmus keratinocytes of the hair follicle activate latent transforming growth factor-β production in the skin, which enhances CD103 expression (Adachi et al., 2015; Casey et al., 2012; El-Asady et al., 2005; Mackay et al., 2013; Masopust et al., 2010; Mohammed et al., 2016).
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The murine skin also contains CD103−CD8+ TRM cells (Mackay et al., 2013), but the underlying mechanisms of their maintenance in the skin are not well understood. CD69 suppresses sphingosine-1-phosphate receptor 1, a molecule known to prevent T cells from emigrating from lymphoid organs or other tissues into the skin (Skon et al., 2013). Furthermore, CCR4 and CD103 expressed by dermal TREG cells are critical to TREG migratory behavior and maintenance in the skin, respectively (Chow et al., 2013; Suffia et al., 2005). Disruption of the skin barrier induces αβ T-cell migration to and from the lymph node, including effector TEFF, regulatory, and central memory T cells (TCM) (Bromley et al., 2013; Mackay et al., 2013; Tomura et al., 2010), and many of them become long-lived antigen-specific skin-resident memory T cells, termed TRM. The critical roles of αβ and γδ T cells in the contexts of defense against skin infections, host-microbiome interactions, and skin damage will be discussed in this review article. J Invest Dermatol. Author manuscript; available in PMC 2017 August 10.
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THE CUTANEOUS T-CELL REPERTOIRE IN HUMAN SKIN
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Both epidermal and dermal γδ and αβ T cells are present in noninflamed human skin;however, cutaneous γδ T cells are approximately 300 times less abundant than αβ T cells (Clark et al., 2006; Streilein, 1983; Toulon et al., 2009; Watanabe et al., 2015). Cutaneous γδ T cells express predominantly the Vδ1 TCR chain and the skin-homing cutaneous lymphocyte antigen (CLA) (Toulon et al., 2009). TRM participate in immunosurveillance because of their robust and long-lasting memory responses and derive from a surviving effector T cells (TEFF) pool. Human skin TRM comprise CD103+ and CD103− subsets;CD103+ T cells are enriched in the epidermis, whereas CD103− TRM are more frequent in the dermis (Watanabe et al., 2015). Recent studies demonstrate that in addition to TRM, there are two subsets of CCR7+ TCM that can also migrate to the skin. One subset coexpresses L-selectin (CD62L), whereas the other subset does not;the latter subset has been termed migratory memory T cells (Park and Kupper, 2015). In addition, healthy human skin also harbors Foxp3+ memory regulatory T cells, termed mTREG cells, residing around hair follicles where they contribute to immune homeostasis, or if dysregulated can mediate immunopathology (Chow et al., 2013; Sanchez Rodriguez et al., 2014; Seneschal et al., 2012). The composition and function of cutaneous T cells can change dramatically on environmental insults and may be driven by both antigen exposure and innate immune signals derived from surrounding keratinocytes, dendritic cells, macrophages, and other cells (Iwasaki and Medzhitov, 2015; Schroder et al., 2006). This review article focuses on the effects of cutaneous T-cell activation in the context of environmental insults and the factors that maintain T cells in the skin to provide long-lived protective functions.
CONTROL OF COMMENSAL AND PATHOGENIC MICROBIOTA BY SKIN T Author Manuscript
CELLS
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The cutaneous microbiome is highly diverse and consists of trillions of bacteria, fungi, viruses, archaea, and small arthropods (Byrd and Segre, 2015; Costello et al., 2009; Grice et al., 2009; Human Microbiome Project Consortium, 2012; Kong and Segre, 2012). The composition of the mouse and human skin microbiome differs extensively in both species, but the microbiome exists without generating a host immunologic response. This concept of host-microbiome tolerance in the skin is supported by a recent study in mice showing that pathogen-specific Foxp3-expressing TREG populate the skin postnatally, at a time where commensal colonization of the skin occurs (Scharschmidt et al., 2015). In contrast, dysbiosis is associated with multiple skin diseases, including atopic eczema, and is associated with dysregulated T-cell function (Kobayashi et al., 2015). In humans, commensal microorganisms inhabit the stratum corneum and hair follicle, and possibly even the deeper dermis (Nakatsuji et al., 2013). Changes in the microbiome occur both physiologically and in the setting of skin disease (Kong et al., 2012; Zeeuwen et al., 2012). Based on recent studies, on one hand, the microbiome can enhance protective immunity against pathogens may be driven by cutaneous T cells (and may include additional immune cells). On the other hand, microbiota fine-tune cutaneous T-cell immunity (Naik et al., 2012). Whether the cutaneous microbiome is regulated by antimicrobial peptides and proteins that are inducible by skin T-cell-derived cytokines, including IL-22 and IL-17A, is of particular interest
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(Eyerich et al., 2009; MacLeod et al., 2013; Naik et al., 2012; Sonnenberg et al., 2011). Furthermore, given the recent discovery of a lipid-reactive and CD1a-restricted skin-homing T-cell population producing high levels of IL-22 (de Jong et al., 2014), future studies to determine whether skin lipids derived from microbiota can directly regulate T-cell homing and maintenance in human skin are needed. Elucidating in detail the functional interactions between microbiome diversity and skin T cells in a steady state and in several skin diseases will provide novel strategies for therapies.
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Multiple mouse models have advanced our understanding of cutaneous protective TRM functions in the context of viral infections, including cutaneous herpes simplex virus (HSV)-1 and vaccinia virus infections. Here, TRM cells reside in the skin during the effector phase of the immune response and persist for several months to provide optimal protection against reinfection by the generation of high levels of IFN-γ. CD8+ TRM primarily accumulate in the epidermis, whereas CD4+ TRM primarily accumulate within the upper dermis (Collins et al., 2016; Gaide et al., 2015; Gebhardt et al., 2009, 2011; Heath and Carbone, 2013; Jiang et al., 2012; Mackay et al., 2012). Keratinocytes are the target cells of most cutaneous viruses; thus, epidermal CD8+ TRM may provide superior protection against viral infections (Mackay et al., 2012; Wakim et al., 2008; Zaid et al., 2014). Epidermal CD8+ TRM residence involves a concomitant local reduction in DETC numbers in the epidermis, indicating that these populations persist in mutual exclusion and may compete for local survival signals (Zaid et al., 2014). Upon viral infection, clusters of IFN-γ-producing CD4+ T cells surrounding hair follicles appear and contain CCL5-producing (APCS), as well CD8+ T cells that increase CD4+ T-cell recruitment into the skin (Collins et al., 2016).
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In contrast to viral infections, immune surveillance against cutaneous bacterial and fungal infections is largely provided by γδ T cells. Here, cutaneous IL-17-producing γδ T cells are critical to combat murine cutaneous Staphylococcus aureus and Candida albicans infections (Cho et al., 2010; Kashem et al., 2015). However, whether previous infections and induction of IL-17-producing T cells lead to generation of long-term “γδ–TRM” and at least partial protection against reinfection is currently unknown.
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The functional roles of TRM in human skin in the context of pathogenic infections have been enhanced by ex vivo and in vitro studies, but they are largely correlative in nature. Human skin from newborns, but not from adults, harbors effector T cells that produce high levels of IL-8 (CXCL8) to activate antimicrobial neutrophils and γδ T cells (Gibbons et al., 2014). Adult CLA+ skin-tropic T cells proliferate strongly in vitro after stimulation with pathogens commonly encountered at the cutaneous epithelial surface, such as S. epidermidis, the herpes simplex virus (HSV)-1, and Candida. Notably, in response to C. albicans stimulation, skin-homing T cells isolated from human blood produce IL-9 to enhance effector function of IL-9-producing T helper type 9 (Th9) cells and other effector T cells. Moreover, these Th9 cells reside in healthy human skin and comprise a small but distinct TRM subset (Schlapbach et al., 2014). Furthermore, staphylococcal exotoxins trigger IL-22 production from skinhoming Th22, indicating their potential role in host defense and triggering skin inflammation (Kobayashi et al., 2015; Niebuhr et al., 2010).
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SKIN T CELLS PROMOTE WOUND HEALING AND RE-ESTABLISH THE ANTIMICROBIAL BARRIER
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Upon skin injury, inflammatory and antimicrobial immune responses are aimed at rapidly clearing microbial contamination before an anti-inflammatory repair program can facilitate wound closure. In mice, γδ T cells, in particular DETCs, have been shown to play critical roles in skin wound repair through recognizing a stress-induced DETC antigen on damaged keratinocytes (Komori et al., 2012), and subsequently stimulating the re-establishment of the skin antimicrobial and physical barrier (Jameson et al., 2002; MacLeod et al., 2013). Whether the previously suggested DETC antigen, Skint-1, truly mediates the stress-induced DETC activation upon wounding needs additional proof, as Skint-1 has not been successfully visualized in the skin nor in the thymus (Barbee et al., 2011). Once activated, a subset of DETCs rapidly produces IL-17A upon skin injury, before the influx of additional peripheral T cells into the skin (Baum and Arpey, 2005; MacLeod et al., 2013), and induces epidermal host-defense molecules, including β-defensin 3, S100A8, and RegIIIg (MacLeod et al., 2013). These antimicrobial peptides and proteins function not only by killing microbes, but also by regulating keratinocyte migration, energy metabolism, cytoskeletal dynamics, and keratinocyte proliferation and differentiation in the skin (Lai et al., 2012; MacLeod et al., 2013; Thorey et al., 2001). Additional cytokines and keratinocyte growth factor are produced by skin-resident γδ T cells in mice to stimulate keratinocyte proliferation (Barbee et al., 2011). Cutaneous TREG cells regulate the transition from wound inflammation to the anti-inflammatory repair phase, as these cells promote wound repair through controlling overt inflammation and proinflammatory macrophage accumulation in murine skin wounds (Nosbaum et al., 2016).
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Human cutaneous αβ and γδ T cells play pivotal roles in wound repair as well. An elegant study by Toulon et al. (2009) demonstrated that αβ and γδ TCR+ skin-resident T cells isolated from acute, but not from nonhealing chronic wounds, produce insulin-like growth factor 1 upon activation to promote wound repair. Furthermore, human cutaneous T helper type 22 cells produce IL-22, IL-17, and other cytokines. They can stimulate keratinocyte production of antimicrobial peptides and proteins and directly induce keratinocyte proliferation, and collagen and fibronectin production (Eyerich et al., 2009; Lai et al., 2012; McGee et al., 2013). Whether TREG cells also control cutaneous wound repair in humans has not been fully elucidated.
SKIN T CELLS AND UV RADIATION Author Manuscript
Solar UV radiation is a major environmental stressor causing skin damage. The major events studied in the skin after UV exposure are induction of DNA damage, inflammation, immunosuppression, and carcinogenesis. The role of skin T cells in UV-irradiated skin is thus very complex and will be summarized here. UV radiation induces DNA damage through creation of photoproducts and reactive oxygen species, either through direct induction of chemical reactions within DNA or through DNAstrand breaks (Barnes et al., 2010; Gehrke et al., 2013; Greinert et al., 2012; Kripke et al., 1992; Lankinen et al., 1996). UVB radiation (290–320 nm wavelength) and wavelengths
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close to the UVB spectrum are particularly associated with DNA damage and carry a high risk of inducing genetic instability and cancer (Rünger, 2013). In vivo mouse studies focusing on responses to acute inflammatory UV-induced DNA damage have identified critical functions of DETCs in epidermal DNA damage repair (MacLeod et al., 2014). Mechanistically, UV-irradiated damaged keratinocytes release ATP, which is sensed by purinergic receptors on DETCs and other skin cells, leading to increased DETC IL-17A production. IL-17A induces an epidermal tumor necrosis factor-related weak inducer of apoptosis and growth arrest, and DNA damage-associated gene 45, these two molecules are linked to the DNA repair response and regulation of cell survival and cell death (Hildesheim et al., 2002; MacLeod et al., 2014; Sabour Alaoui et al., 2012). Although this study suggests that DETCs can reduce keratinocyte DNA damage, by limiting γH2AX and cyclobutane pyrimidine dimers, early on, a recent study by Girardi’s group reported that once UVinduced p53 mutations in keratinocytes are acquired, T cells may not be critical in controlling Langerhans cell-driven expansion of these p53 mutant clones (Lewis et al., 2015). However, given the protective cytotoxic role of effector and memory T cells in cancer immunosurveillance (Girardi et al., 2001; Nasti et al., 2011; Strid et al., 2008) and the induction of TREG cells by UV-associated with immunosuppression (Schwarz et al., 2011), it remains to be determined which roles αβ versus γδ T cells play at distinct stages of skin cancer initiation, promotion, and progression.
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UV radiation has dramatic tolerogenic and immunosuppressive effects on T cells, both locally and systemically. Elegant studies performed in mice have shown that UV-induced tolerance involves the suppression of cutaneous CD4+ and CD8+ effector functions, and this increases TREG activity in the context of allergic contact hypersensitivity and transplantable tumor models (Rana et al., 2008; Schwarz et al., 2005, 2011; Toichi et al., 2002). Together, these studies indicate that maintaining genome integrity in the setting of UV-induced DNA damage, as well as additional immune-protective cytotoxic T-cell functions, is vital for the prevention of early tumor initiation and these protective responses are likely suppressed during skin carcinogenesis (Girardi et al., 2001; MacLeod et al., 2014).
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Human cutaneous T-cell responses to acute and chronic UV radiation show some parallels to those observed in mice. Both tumor necrosis factor-related weak inducer of apoptosis and growth arrest and DNA damage-associated gene 45 playa role in human skin homeostasis (Maeda et al., 2003; Sabour Alaoui et al., 2012) and are induced by T-cell-derived IL-17A (MacLeod et al., 2014). IL-17A generation is stimulated from human cutaneous TRM by extracellular ATP, a danger signal released upon UV damage (MacLeod et al., 2014). However, future studies will need to clarify in detail the role of human T cells in keratinocyte DNA damage response and how these processes are suppressed in UV-induced skin cancers, such as squamous cell carcinomas and basal cell carcinomas. Similar to mice, UV exposure sufficiently suppresses T-cell-mediated elicitation reactions of contact hypersensitivity responses in human skin (Cooper et al., 1992; Kelly et al., 1998), indicating that there are strong tolerogenic effects of UV on cutaneous TRM. These effects may directly contribute to the development of human squamous cell carcinomas, which are characterized by numeric and qualitative changes of TRM in the skin with increased frequency of TREG cells (Clark et al., 2008; McCray et al., 2015). Because TRM differ between humans and mice (see Table 1), determining which subsets of human cutaneous T cells distinctly J Invest Dermatol. Author manuscript; available in PMC 2017 August 10.
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contribute to skin cancer suppression and promotion, and identification of the molecular mechanisms will allow novel targeted therapies.
PATHOLOGIC ROLES FOR SKIN T CELLS IN HYPERSENSITIVITY REACTIONS TO CONTACT ALLERGEN AND DRUGS
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Environmental contact allergens such as nickel, perfumes, latex, and poison ivy, can result in T-cell-driven skin inflammation, commonly known as allergic contact dermatitis. Murine delayed contact hypersensitivity (CHS) is an experimental model of human allergic contact dermatitis and consists of two separate phases: sensitization and elicitation (He et al., 2009; Heo et al., 2015; Wang et al., 2000; Xu et al., 1996). The initial sensitization phase is characterized by the formation of complexes between allergens and epidermal proteins, which are subsequently taken up and presented by APCs. These APCs migrate to the draining lymph nodes to present these complexes to naïve T cells, leading them to differentiate into TCM and TRM. These TCM and TRM cells have overlapping TCR repertoires (Gaide et al., 2015) and serve as the major effector cells for mediating the robust inflammatory damaging response in the elicitation phase of CHS. Notably, despite identical TCRs, TRM have a stronger and more rapid response than TCM after re-exposure to the same contact allergen (Gaide et al., 2015). Whether this is simply the result of distinct anatomic locations is currently unknown. In addition to αβ T cells, γδ T cells also play important roles in the murine CHS response. Upon contact allergen exposure, keratinocyte-derived IL-1β triggers IL-17A production in DETCs to mediate inflammation (Nielsen et al., 2014). In contrast, TREG cells serve an immunosuppressive function and negatively regulate the CHS responses via the suppression of T-cell effector functions (Christensen et al., 2015; Gomez de Aguero et al., 2012; Honda et al., 2010). Whether langerin-expressing Langerhans cells, the enigmatic dendritic cell population within the epidermis, or langerin+ dermal dendritic cells activate TREG and play suppressive roles in CHS, or are relevant as APCs at the sensitization phase, remains a matter of debate. Differences and paradoxical findings, however, may be due to differences in allergen applications and/or the timing of ablation of langerin+ cells via diphtheria toxin in the CHS model using langerin-diphtheria toxin receptor (DTR) mice (Bennet et al., 2005, 2007; Gomez de Aguero et al., 2012; Honda et al., 2010; Kaplan et al., 2005; Kissenpfennig et al., 2005).
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In human skin, CD4+ Th1 and Th2 subsets, along with CD8+ T cells, serve as effector cells in allergic contact dermatitis (Cavani et al., 2001);however, the role of γδ T cells in allergic contact dermatitis in humans is still poorly understood. Notably, cutaneous T cells mediate damage to epidermal keratinocytes, a phenomenon also observed in fixed drug eruptions (FDEs). FDEs are skin lesions occurring after repeated ingestion of causative drugs, and similar to a contact allergy, FDE resembles a cytotoxic reaction of cutaneous CD8+ T cells against epidermal keratinocytes in human skin. Of note, new FDE lesions often develop at the site of a previous viral infection, suggesting that protective antiviral long-lived CD8+ TRM cells in the skin may be reactivated by antigen cross-presentation to subsequently induce FDE lesions. However, FDE cannot be considered a true delayed type IV allergy response such as allergic contact dermatitis, and is instead characterized by the “conversion”
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of lesional CD8+CD45RO+ TRM into CD8+CD45Ra+ T cells in clinically resolved skin (Shiohara et al., 2015).
CONCLUSIONS
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Functional studies in mice and humans have highlighted the relevance of T cells in cutaneous immunology and maintenance of the body’s first line of defense. Cutaneous memory T cells play pivotal effector roles as “gate keepers” against environmental insults through regulation and protection against microbes, injury, and cancer development. TREG are critical in maintaining immune tolerance against self-antigens and promoting skin repair. Dysregulation and overly vigorous activation of skin T cells can cause detrimental effects, resulting in skin pathology. The heterogeneity of skin T cells is just beginning to be understood, and future studies are required to further define skin T-cell subsets and their anatomical, structural, and functional relationships. Novel therapeutic strategies to either inhibit or augment skin T-cell function are being developed for clinical use, and specific targeting of these cells holds promise for the treatment of a variety of human skin conditions, including autoimmune diseases, infections, and cancer.
Acknowledgments We apologize to all authors whose work could not be cited here due to space limitations. ASM is supported by the NIH through award K08AR063729 05. As a Duke Cancer Institute member, we gratefully acknowledge grantsupport from the Duke Cancer Institute (to ASM) as part of the P30 Cancer Center Support Grant (P30CA014236). As a member of the Skin Disease Research Center and Pinnell Center for Investigative Dermatology, we gratefully acknowledge grant support (to ASM) from the Duke Skin Disease Research Center (P30AR066527 02) and Pinnell Center for Investigative Dermatology and Skin Disease Research Center at Duke University Medical Center.
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Abbreviations
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APC
antigen-presenting cell
CHS
contact hypersensitivity
CLA
cutaneous lymphocyte-associated antigen
DETC
dendritic epidermal T cell
FDE
fixed drug eruption
TCM
central memory T cell
TEFF
effector T cell
Th
T helper
TREG
regulatory T cell
TRM
tissue-resident memory T cell
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Figure 1. Murine and human skin harbors T cells
The illustration of diverse cutaneous T cell populations in the human and mouse. DETC, dendritic epidermal T cell; TRM, tissue-resident memory T cell.
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Table 1
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Heterogeneity of human and murine skin resident T cells Location
T-cell subset
Mouse
Epidermis
γδ T cells
Epidermis
CD4+ T cell
CD103+ > CD103− TRM
CD103+ > CD103− TRM
Epidermis
CD4+ TREG
FoxP3+ TREG
FoxP3+ TREG
Epidermis
CD8+ T cell
CD103+ > CD103− TRM
CD103+ > CD103− TRM
Dermis
γδ T cells
Vγ4−/+
Vδ1+ enriched
Dermis
CD4+ T cell
FoxP3− TRM
CD103− > CD103+ TRM
Dermis
CD4+ TREG
FoxP3+ mTREG
FoxP3+ TREG
Dermis
CD8+ T cell
CD103− > CD103+ TRM
CD103− > CD103+ TRM
DETC
(Vγ3+Vδ1+)
Human Vδ1+ enriched
Author Manuscript
Abbreviations: DETC, dendritic epidermal T cell; TREG, regulatory T cell; TRM, tissue-resident memory T cell.
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