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γδ T Cells

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Immunology of the Skin

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Abstract

γδ T cells represent a minor population of T cells in the peripheral blood and lymphoid tissues in both mice and humans, but are abundant in certain epithelial tissues including the skin, especially in mice. In contrast to conventional αβ T cells with the diverse T-cell receptor (TCR) repertoire for adaptive immunity, epithelial γδ T cells express tissue-specific invariant or restricted TCRs and have innate-like properties. Dendritic epidermal T cells (DETCs) that reside in the murine epidermis and express an invariant γδ TCR are prototypic epithelial γδ T cells. DETCs mediate stress surveillance in the epidermis, and play key roles in immunoregulation, wound healing, epidermal homeostasis, hair cycle regulation, and tumor surveillance. Recently, a novel subset of γδ T cells residing in the murine dermis has been identified. Resident murine dermal γδ T cells preferentially produce IL-17, and are essential for defense against cutaneous infection and also for development of psoriasiform dermatitis. γδ T cells are infrequent in the human skin, but Vδ1 TCR-expressing T cells with functional similarities to murine epithelial γδ T cells are present in the normal human skin (mainly in the dermis). Vγ9Vδ2 T cells that are the major circulating γδ T cells in the human peripheral blood can migrate to the inflamed skin, and contribute to immunity against pathogens and tumors, and development of inflammatory skin diseases.

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References

  1. Witherden DA, Havran WL (2011) Molecular aspects of epithelial gammadelta T cell regulation. Trends Immunol 32:265–271

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Macleod AS, Havran WL (2011) Functions of skin-resident gammadelta T cells. Cell Mol Life Sci 68:2399–2408

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Sumaria N, Roediger B, Ng LG, Qin J, Pinto R, Cavanagh LL, Shklovskaya E, Fazekas de St Groth B, Triccas JA, Weninger W (2011) Cutaneous immunosurveillance by self-renewing dermal gammadelta T cells. J Exp Med 208:505–518

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Cai Y, Shen X, Ding C, Qi C, Li K, Li X, Jala VR, Zhang HG, Wang T, Zheng J, Yan J (2011) Pivotal role of dermal IL-17-producing gammadelta T cells in skin inflammation. Immunity 35:596–610

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Dupuy P, Heslan M, Fraitag S, Hercend T, Dubertret L, Bagot M (1990) T-cell receptor-gamma/delta bearing lymphocytes in normal and inflammatory human skin. J Invest Dermatol 94:764–768

    Article  CAS  PubMed  Google Scholar 

  6. Bos JD, Teunissen MB, Cairo I, Krieg SR, Kapsenberg ML, Das PK, Borst J (1990) T-cell receptor gamma delta bearing cells in normal human skin. J Invest Dermatol 94:37–42

    Article  CAS  PubMed  Google Scholar 

  7. Foster CA, Yokozeki H, Rappersberger K, Koning F, Volc-Platzer B, Rieger A, Coligan JE, Wolff K, Stingl G (1990) Human epidermal T cells predominantly belong to the lineage expressing alpha/beta T cell receptor. J Exp Med 171:997–1013

    Article  CAS  PubMed  Google Scholar 

  8. Toulon A, Breton L, Taylor KR, Tenenhaus M, Bhavsar D, Lanigan C, Rudolph R, Jameson J, Havran WL (2009) A role for human skin-resident T cells in wound healing. J Exp Med 206:743–750

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Ebert LM, Meuter S, Moser B (2006) Homing and function of human skin gammadelta T cells and NK cells: relevance for tumor surveillance. J Immunol 176:4331–4336

    Article  CAS  PubMed  Google Scholar 

  10. Hayday AC (2009) Gammadelta T cells and the lymphoid stress-surveillance response. Immunity 31:184–196

    Article  CAS  PubMed  Google Scholar 

  11. Bonneville M, O’Brien RL, Born WK (2010) Gammadelta T cell effector functions: a blend of innate programming and acquired plasticity. Nat Rev Immunol 10:467–478

    Article  CAS  PubMed  Google Scholar 

  12. Garman RD, Doherty PJ, Raulet DH (1986) Diversity, rearrangement, and expression of murine T cell gamma genes. Cell 45:733–742

    Article  CAS  PubMed  Google Scholar 

  13. Allison JP, Havran WL (1991) The immunobiology of T cells with invariant gamma delta antigen receptors. Annu Rev Immunol 9:679–705

    Article  CAS  PubMed  Google Scholar 

  14. Haas JD, Ravens S, Duber S, Sandrock I, Oberdorfer L, Kashani E, Chennupati V, Fohse L, Naumann R, Weiss S, Krueger A, Forster R, Prinz I (2012) Development of interleukin-17-producing gammadelta T cells is restricted to a functional embryonic wave. Immunity 37:48–59

    Article  CAS  PubMed  Google Scholar 

  15. Prinz I, Silva-Santos B, Pennington DJ (2013) Functional development of gammadelta T cells. Eur J Immunol 43:1988–1994

    Article  CAS  PubMed  Google Scholar 

  16. Heilig JS, Tonegawa S (1986) Diversity of murine gamma genes and expression in fetal and adult T lymphocytes. Nature 322:836–840

    Article  CAS  PubMed  Google Scholar 

  17. Havran WL, Allison JP (1990) Origin of Thy-1+ dendritic epidermal cells of adult mice from fetal thymic precursors. Nature 344:68–70

    Article  CAS  PubMed  Google Scholar 

  18. Payer E, Elbe A, Stingl G (1991) Circulating CD3+/T cell receptor V gamma 3+ fetal murine thymocytes home to the skin and give rise to proliferating dendritic epidermal T cells. J Immunol 146:2536–2543

    CAS  PubMed  Google Scholar 

  19. Havran WL, Allison JP (1988) Developmentally ordered appearance of thymocytes expressing different T-cell antigen receptors. Nature 335:443–445

    Article  CAS  PubMed  Google Scholar 

  20. Havran WL, Grell S, Duwe G, Kimura J, Wilson A, Kruisbeek AM, O’Brien RL, Born W, Tigelaar RE, Allison JP (1989) Limited diversity of T-cell receptor gamma-chain expression of murine Thy-1+ dendritic epidermal cells revealed by V gamma 3-specific monoclonal antibody. Proc Natl Acad Sci U S A 86:4185–4189

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Itohara S, Farr AG, Lafaille JJ, Bonneville M, Takagaki Y, Haas W, Tonegawa S (1990) Homing of a gamma delta thymocyte subset with homogeneous T-cell receptors to mucosal epithelia. Nature 343:754–757

    Article  CAS  PubMed  Google Scholar 

  22. Shibata K, Yamada H, Nakamura R, Sun X, Itsumi M, Yoshikai Y (2008) Identification of CD25+ gamma delta T cells as fetal thymus-derived naturally occurring IL-17 producers. J Immunol 181:5940–5947

    Article  CAS  PubMed  Google Scholar 

  23. Kisielow J, Kopf M, Karjalainen K (2008) SCART scavenger receptors identify a novel subset of adult gammadelta T cells. J Immunol 181:1710–1716

    Article  CAS  PubMed  Google Scholar 

  24. Xiong N, Raulet DH (2007) Development and selection of gammadelta T cells. Immunol Rev 215:15–31

    Article  CAS  PubMed  Google Scholar 

  25. Narayan K, Sylvia KE, Malhotra N, Yin CC, Martens G, Vallerskog T, Kornfeld H, Xiong N, Cohen NR, Brenner MB, Berg LJ, Kang J (2012) Intrathymic programming of effector fates in three molecularly distinct gammadelta T cell subtypes. Nat Immunol 13:511–518

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Pang DJ, Neves JF, Sumaria N, Pennington DJ (2012) Understanding the complexity of gammadelta T-cell subsets in mouse and human. Immunology 136:283–290

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Fahl SP, Coffey F, Wiest DL (2014) Origins of gammadelta T cell effector subsets: a riddle wrapped in an enigma. J Immunol 193:4289–4294

    Article  CAS  PubMed  Google Scholar 

  28. Leclercq G, Plum J, Nandi D, De Smedt M, Allison JP (1993) Intrathymic differentiation of V gamma 3 T cells. J Exp Med 178:309–315

    Article  CAS  PubMed  Google Scholar 

  29. Kawai K, Kishihara K, Molina TJ, Wallace VA, Mak TW, Ohashi PS (1995) Impaired development of V gamma 3 dendritic epidermal T cells in p56lck protein tyrosine kinase-deficient and CD45 protein tyrosine phosphatase-deficient mice. J Exp Med 181:345–349

    Article  CAS  PubMed  Google Scholar 

  30. Ferrero I, Wilson A, Beermann F, Held W, MacDonald HR (2001) T cell receptor specificity is critical for the development of epidermal gammadelta T cells. J Exp Med 194:1473–1483

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Lewis JM, Girardi M, Roberts SJ, Barbee SD, Hayday AC, Tigelaar RE (2006) Selection of the cutaneous intraepithelial gammadelta+ T cell repertoire by a thymic stromal determinant. Nat Immunol 7:843–850

    Article  CAS  PubMed  Google Scholar 

  32. Boyden LM, Lewis JM, Barbee SD, Bas A, Girardi M, Hayday AC, Tigelaar RE, Lifton RP (2008) Skint1, the prototype of a newly identified immunoglobulin superfamily gene cluster, positively selects epidermal gammadelta T cells. Nat Genet 40:656–662

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Barbee SD, Woodward MJ, Turchinovich G, Mention JJ, Lewis JM, Boyden LM, Lifton RP, Tigelaar R, Hayday AC (2011) Skint-1 is a highly specific, unique selecting component for epidermal T cells. Proc Natl Acad Sci U S A 108:3330–3335

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Turchinovich G, Hayday AC (2011) Skint-1 identifies a common molecular mechanism for the development of interferon-gamma-secreting versus interleukin-17-secreting gammadelta T cells. Immunity 35:59–68

    Article  CAS  PubMed  Google Scholar 

  35. Xiong N, Kang C, Raulet DH (2004) Positive selection of dendritic epidermal gammadelta T cell precursors in the fetal thymus determines expression of skin-homing receptors. Immunity 21:121–131

    Article  CAS  PubMed  Google Scholar 

  36. Xia M, Qi Q, Jin Y, Wiest DL, August A, Xiong N (2010) Differential roles of IL-2-inducible T cell kinase-mediated TCR signals in tissue-specific localization and maintenance of skin intraepithelial T cells. J Immunol 184:6807–6814

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Jin Y, Xia M, Saylor CM, Narayan K, Kang J, Wiest DL, Wang Y, Xiong N (2010) Cutting edge: intrinsic programming of thymic gammadeltaT cells for specific peripheral tissue localization. J Immunol 185:7156–7160

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Leclercq G, De Smedt M, Plum J (1995) Cytokine dependence of V gamma 3 thymocytes: mature but not immature V gamma 3 cells require endogenous IL-2 and IL-7 to survive – evidence for cytokine redundancy. Int Immunol 7:843–851

    Article  CAS  PubMed  Google Scholar 

  39. Jin Y, Xia M, Sun A, Saylor CM, Xiong N (2010) CCR10 is important for the development of skin-specific gammadeltaT cells by regulating their migration and location. J Immunol 185:5723–5731

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Kawai K, Suzuki H, Tomiyama K, Minagawa M, Mak TW, Ohashi PS (1998) Requirement of the IL-2 receptor beta chain for the development of Vgamma3 dendritic epidermal T cells. J Invest Dermatol 110:961–965

    Article  CAS  PubMed  Google Scholar 

  41. De Creus A, Van Beneden K, Stevenaert F, Debacker V, Plum J, Leclercq G (2002) Developmental and functional defects of thymic and epidermal V gamma 3 cells in IL-15-deficient and IFN regulatory factor-1-deficient mice. J Immunol 168:6486–6493

    Article  PubMed  Google Scholar 

  42. Macleod AS, Hemmers S, Garijo O, Chabod M, Mowen K, Witherden DA, Havran WL (2013) Dendritic epidermal T cells regulate skin antimicrobial barrier function. J Clin Invest 123:4364–4374

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Azuara V, Levraud JP, Lembezat MP, Pereira P (1997) A novel subset of adult gamma delta thymocytes that secretes a distinct pattern of cytokines and expresses a very restricted T cell receptor repertoire. Eur J Immunol 27:544–553

    Article  CAS  PubMed  Google Scholar 

  44. Gerber DJ, Azuara V, Levraud JP, Huang SY, Lembezat MP, Pereira P (1999) IL-4-producing gamma delta T cells that express a very restricted TCR repertoire are preferentially localized in liver and spleen. J Immunol 163:3076–3082

    CAS  PubMed  Google Scholar 

  45. Azuara V, Grigoriadou K, Lembezat MP, Nagler-Anderson C, Pereira P (2001) Strain-specific TCR repertoire selection of IL-4-producing Thy-1 dull gamma delta thymocytes. Eur J Immunol 31:205–214

    Article  CAS  PubMed  Google Scholar 

  46. Jensen KD, Su X, Shin S, Li L, Youssef S, Yamasaki S, Steinman L, Saito T, Locksley RM, Davis MM, Baumgarth N, Chien YH (2008) Thymic selection determines gammadelta T cell effector fate: antigen-naive cells make interleukin-17 and antigen-experienced cells make interferon gamma. Immunity 29:90–100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Azuara V, Lembezat MP, Pereira P (1998) The homogeneity of the TCRdelta repertoire expressed by the Thy-1dull gammadelta T cell population is due to cellular selection. Eur J Immunol 28:3456–3467

    Article  CAS  PubMed  Google Scholar 

  48. Kreslavsky T, Savage AK, Hobbs R, Gounari F, Bronson R, Pereira P, Pandolfi PP, Bendelac A, von Boehmer H (2009) TCR-inducible PLZF transcription factor required for innate phenotype of a subset of gammadelta T cells with restricted TCR diversity. Proc Natl Acad Sci U S A 106:12453–12458

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Ribot JC, deBarros A, Pang DJ, Neves JF, Peperzak V, Roberts SJ, Girardi M, Borst J, Hayday AC, Pennington DJ, Silva-Santos B (2009) CD27 is a thymic determinant of the balance between interferon-gamma- and interleukin 17-producing gammadelta T cell subsets. Nat Immunol 10:427–436

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Haas JD, Gonzalez FH, Schmitz S, Chennupati V, Fohse L, Kremmer E, Forster R, Prinz I (2009) CCR6 and NK1.1 distinguish between IL-17A and IFN-gamma-producing gammadelta effector T cells. Eur J Immunol 39:3488–3497

    Article  CAS  PubMed  Google Scholar 

  51. Gray EE, Suzuki K, Cyster JG (2011) Cutting edge: identification of a motile IL-17-producing gammadelta T cell population in the dermis. J Immunol 186:6091–6095

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Itohara S, Tonegawa S (1990) Selection of gamma delta T cells with canonical T-cell antigen receptors in fetal thymus. Proc Natl Acad Sci U S A 87:7935–7938

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Michel ML, Pang DJ, Haque SF, Potocnik AJ, Pennington DJ, Hayday AC (2012) Interleukin 7 (IL-7) selectively promotes mouse and human IL-17-producing gammadelta cells. Proc Natl Acad Sci U S A 109:17549–17554

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Mahtani-Patching J, Neves JF, Pang DJ, Stoenchev KV, Aguirre-Blanco AM, Silva-Santos B, Pennington DJ (2011) PreTCR and TCRgammadelta signal initiation in thymocyte progenitors does not require domains implicated in receptor oligomerization. Sci Signal 4:ra47

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Turchinovich G, Pennington DJ (2011) T cell receptor signalling in gammadelta cell development: strength isn’t everything. Trends Immunol 32:567–573

    Article  CAS  PubMed  Google Scholar 

  56. Cheroutre H, Lambolez F, Mucida D (2011) The light and dark sides of intestinal intraepithelial lymphocytes. Nat Rev Immunol 11:445–456

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Lin T, Matsuzaki G, Kenai H, Nakamura T, Nomoto K (1993) Thymus influences the development of extrathymically derived intestinal intraepithelial lymphocytes. Eur J Immunol 23:1968–1974

    Article  CAS  PubMed  Google Scholar 

  58. Sugahara S, Shimizu T, Yoshida Y, Aiba T, Yamagiwa S, Asakura H, Abo T (1999) Extrathymic derivation of gut lymphocytes in parabiotic mice. Immunology 96:57–65

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Saito H, Kanamori Y, Takemori T, Nariuchi H, Kubota E, Takahashi-Iwanaga H, Iwanaga T, Ishikawa H (1998) Generation of intestinal T cells from progenitors residing in gut cryptopatches. Science 280:275–278

    Article  CAS  PubMed  Google Scholar 

  60. Peaudecerf L, dos Santos PR, Boudil A, Ezine S, Pardigon N, Rocha B (2011) The role of the gut as a primary lymphoid organ: CD8alphaalpha intraepithelial T lymphocytes in euthymic mice derive from very immature CD44+ thymocyte precursors. Mucosal Immunol 4:93–101

    Article  CAS  PubMed  Google Scholar 

  61. Chen Y, Chou K, Fuchs E, Havran WL, Boismenu R (2002) Protection of the intestinal mucosa by intraepithelial gamma delta T cells. Proc Natl Acad Sci U S A 99:14338–14343

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Havran WL, Chien YH, Allison JP (1991) Recognition of self antigens by skin-derived T cells with invariant gamma delta antigen receptors. Science 252:1430–1432

    Article  CAS  PubMed  Google Scholar 

  63. Aydintug MK, Roark CL, Yin X, Wands JM, Born WK, O’Brien RL (2004) Detection of cell surface ligands for the gamma delta TCR using soluble TCRs. J Immunol 172:4167–4175

    Article  CAS  PubMed  Google Scholar 

  64. Komori HK, Witherden DA, Kelly R, Sendaydiego K, Jameson JM, Teyton L, Havran WL (2012) Cutting edge: dendritic epidermal gammadelta T cell ligands are rapidly and locally expressed by keratinocytes following cutaneous wounding. J Immunol 188:2972–2976

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Ibusuki A, Kawai K, Yoshida S, Uchida Y, Nitahara-Takeuchi A, Kuroki K, Kajikawa M, Ose T, Maenaka K, Kasahara M, Kanekura T (2013) NKG2D triggers cytotoxicity in murine epidermal gammadelta T cells via PI3K-dependent, Syk/ZAP70-independent signaling pathway. J Invest Dermatol 134:396–404

    Article  PubMed  CAS  Google Scholar 

  66. Mallick-Wood CA, Lewis JM, Richie LI, Owen MJ, Tigelaar RE, Hayday AC (1998) Conservation of T cell receptor conformation in epidermal gammadelta cells with disrupted primary Vgamma gene usage. Science 279:1729–1733

    Article  CAS  PubMed  Google Scholar 

  67. Hara H, Kishihara K, Matsuzaki G, Takimoto H, Tsukiyama T, Tigelaar RE, Nomoto K (2000) Development of dendritic epidermal T cells with a skewed diversity of gamma delta TCRs in V delta 1-deficient mice. J Immunol 165:3695–3705

    Article  CAS  PubMed  Google Scholar 

  68. Aono A, Enomoto H, Yoshida N, Yoshizaki K, Kishimoto T, Komori T (2000) Forced expression of terminal deoxynucleotidyl transferase in fetal thymus resulted in a decrease in gammadelta T cells and random dissemination of Vgamma3Vdelta1 T cells in skin of newborn but not adult mice. Immunology 99:489–497

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Minagawa M, Ito A, Shimura H, Tomiyama K, Ito M, Kawai K (2001) Homogeneous epithelial gamma delta T cell repertoire of the skin is shaped through peripheral selection. J Dermatol Sci 25:150–155

    Article  CAS  PubMed  Google Scholar 

  70. Jameson JM, Cauvi G, Witherden DA, Havran WL (2004) A keratinocyte-responsive gamma delta TCR is necessary for dendritic epidermal T cell activation by damaged keratinocytes and maintenance in the epidermis. J Immunol 172:3573–3579

    Article  CAS  PubMed  Google Scholar 

  71. Leandersson K, Jaensson E, Ivars F (2006) T cells developing in fetal thymus of T-cell receptor alpha-chain transgenic mice colonize gammadelta T-cell-specific epithelial niches but lack long-term reconstituting potential. Immunology 119:134–142

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Chodaczek G, Papanna V, Zal MA, Zal T (2012) Body-barrier surveillance by epidermal gammadelta TCRs. Nat Immunol 13:272–282

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Witherden DA, Verdino P, Rieder SE, Garijo O, Mills RE, Teyton L, Fischer WH, Wilson IA, Havran WL (2010) The junctional adhesion molecule JAML is a costimulatory receptor for epithelial gammadelta T cell activation. Science 329:1205–1210

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Witherden DA, Watanabe M, Garijo O, Rieder SE, Sarkisyan G, Cronin SJ, Verdino P, Wilson IA, Kumanogoh A, Kikutani H, Teyton L, Fischer WH, Havran WL (2012) The CD100 receptor interacts with its plexin B2 ligand to regulate epidermal gammadelta T cell function. Immunity 37:314–325

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Girardi M, Oppenheim DE, Steele CR, Lewis JM, Glusac E, Filler R, Hobby P, Sutton B, Tigelaar RE, Hayday AC (2001) Regulation of cutaneous malignancy by gammadelta T cells. Science 294:605–609

    Article  CAS  PubMed  Google Scholar 

  76. Jamieson AM, Diefenbach A, McMahon CW, Xiong N, Carlyle JR, Raulet DH (2002) The role of the NKG2D immunoreceptor in immune cell activation and natural killing. Immunity 17:19–29

    Article  CAS  PubMed  Google Scholar 

  77. Van Beneden K, De Creus A, Stevenaert F, Debacker V, Plum J, Leclercq G (2002) Expression of inhibitory receptors Ly49E and CD94/NKG2 on fetal thymic and adult epidermal TCR V gamma 3 lymphocytes. J Immunol 168:3295–3302

    Article  PubMed  Google Scholar 

  78. Uchida Y, Kawai K, Ibusuki A, Kanekura T (2011) Role for E-cadherin as an inhibitory receptor on epidermal gammadelta T cells. J Immunol 186:6945–6954

    Article  CAS  PubMed  Google Scholar 

  79. Matsue H, Cruz PD Jr, Bergstresser PR, Takashima A (1993) Profiles of cytokine mRNA expressed by dendritic epidermal T cells in mice. J Invest Dermatol 101:537–542

    Article  CAS  PubMed  Google Scholar 

  80. Boismenu R, Feng L, Xia YY, Chang JC, Havran WL (1996) Chemokine expression by intraepithelial gamma delta T cells. Implications for the recruitment of inflammatory cells to damaged epithelia. J Immunol 157:985–992

    CAS  PubMed  Google Scholar 

  81. Nielsen MM, Lovato P, MacLeod AS, Witherden DA, Skov L, Dyring-Andersen B, Dabelsteen S, Woetmann A, Odum N, Havran WL, Geisler C, Bonefeld CM (2014) IL-1beta-dependent activation of dendritic epidermal T cells in contact hypersensitivity. J Immunol 192:2975–2983

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Strid J, Sobolev O, Zafirova B, Polic B, Hayday A (2011) The intraepithelial T cell response to NKG2D-ligands links lymphoid stress surveillance to atopy. Science 334:1293–1297

    Article  CAS  PubMed  Google Scholar 

  83. Shiohara T, Moriya N, Hayakawa J, Itohara S, Ishikawa H (1996) Resistance to cutaneous graft-vs.-host disease is not induced in T cell receptor delta gene-mutant mice. J Exp Med 183:1483–1489

    Article  CAS  PubMed  Google Scholar 

  84. Girardi M, Lewis J, Glusac E, Filler RB, Geng L, Hayday AC, Tigelaar RE (2002) Resident skin-specific gammadelta T cells provide local, nonredundant regulation of cutaneous inflammation. J Exp Med 195:855–867

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Jameson J, Ugarte K, Chen N, Yachi P, Fuchs E, Boismenu R, Havran WL (2002) A role for skin gammadelta T cells in wound repair. Science 296:747–749

    Article  CAS  PubMed  Google Scholar 

  86. Sharp LL, Jameson JM, Cauvi G, Havran WL (2005) Dendritic epidermal T cells regulate skin homeostasis through local production of insulin-like growth factor 1. Nat Immunol 6:73–79

    Article  CAS  PubMed  Google Scholar 

  87. Yoshida S, Mohamed RH, Kajikawa M, Koizumi J, Tanaka M, Fugo K, Otsuka N, Maenaka K, Yagita H, Chiba H, Kasahara M (2012) Involvement of an NKG2D ligand H60c in epidermal dendritic T cell-mediated wound repair. J Immunol 188:3972–3979

    Article  CAS  PubMed  Google Scholar 

  88. Jung H, Hsiung B, Pestal K, Procyk E, Raulet DH (2012) RAE-1 ligands for the NKG2D receptor are regulated by E2F transcription factors, which control cell cycle entry. J Exp Med 209:2409–2422

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Girardi M, Lewis JM, Filler RB, Hayday AC, Tigelaar RE (2006) Environmentally responsive and reversible regulation of epidermal barrier function by gammadelta T cells. J Invest Dermatol 126:808–814

    Article  CAS  PubMed  Google Scholar 

  90. Taylor KR, Costanzo AE, Jameson JM (2011) Dysfunctional gammadelta T cells contribute to impaired keratinocyte homeostasis in mouse models of obesity. J Invest Dermatol 131:2409–2418

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Kloepper JE, Kawai K, Bertolini M, Kanekura T, Paus R (2013) Loss of gammadelta T cells results in hair cycling defects. J Invest Dermatol 133:1666–1669

    Article  CAS  PubMed  Google Scholar 

  92. Kaminski MJ, Cruz PD Jr, Bergstresser PR, Takashima A (1993) Killing of skin-derived tumor cells by mouse dendritic epidermal T-cells. Cancer Res 53:4014–4019

    CAS  PubMed  Google Scholar 

  93. Strid J, Roberts SJ, Filler RB, Lewis JM, Kwong BY, Schpero W, Kaplan DH, Hayday AC, Girardi M (2008) Acute upregulation of an NKG2D ligand promotes rapid reorganization of a local immune compartment with pleiotropic effects on carcinogenesis. Nat Immunol 9:146–154

    Article  CAS  PubMed  Google Scholar 

  94. Nitahara A, Shimura H, Ito A, Tomiyama K, Ito M, Kawai K (2006) NKG2D ligation without T cell receptor engagement triggers both cytotoxicity and cytokine production in dendritic epidermal T cells. J Invest Dermatol 126:1052–1058

    Article  CAS  PubMed  Google Scholar 

  95. Whang MI, Guerra N, Raulet DH (2009) Costimulation of dendritic epidermal gammadelta T cells by a new NKG2D ligand expressed specifically in the skin. J Immunol 182:4557–4564

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Gray EE, Ramirez-Valle F, Xu Y, Wu S, Wu Z, Karjalainen KE, Cyster JG (2013) Deficiency in IL-17-committed Vgamma4(+) gammadelta T cells in a spontaneous Sox13-mutant CD45.1(+) congenic mouse substrain provides protection from dermatitis. Nat Immunol 14:584–592

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Gay D, Kwon O, Zhang Z, Spata M, Plikus MV, Holler PD, Ito M, Yang Z, Treffeisen E, Kim CD, Nace A, Zhang X, Baratono S, Wang F, Ornitz DM, Millar SE, Cotsarelis G (2013) Fgf9 from dermal gammadelta T cells induces hair follicle neogenesis after wounding. Nat Med 19:916–923

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Myles IA, Fontecilla NM, Valdez PA, Vithayathil PJ, Naik S, Belkaid Y, Ouyang W, Datta SK (2013) Signaling via the IL-20 receptor inhibits cutaneous production of IL-1beta and IL-17A to promote infection with methicillin-resistant Staphylococcus aureus. Nat Immunol 14:804–811

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Molne L, Corthay A, Holmdahl R, Tarkowski A (2003) Role of gamma/delta T cell receptor-expressing lymphocytes in cutaneous infection caused by Staphylococcus aureus. Clin Exp Immunol 132:209–215

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Cho JS, Pietras EM, Garcia NC, Ramos RI, Farzam DM, Monroe HR, Magorien JE, Blauvelt A, Kolls JK, Cheung AL, Cheng G, Modlin RL, Miller LS (2010) IL-17 is essential for host defense against cutaneous Staphylococcus aureus infection in mice. J Clin Invest 120:1762–1773

    Article  PubMed  PubMed Central  Google Scholar 

  101. Mabuchi T, Takekoshi T, Hwang ST (2011) Epidermal CCR6+ gammadelta T cells are major producers of IL-22 and IL-17 in a murine model of psoriasiform dermatitis. J Immunol 187:5026–5031

    Article  CAS  PubMed  Google Scholar 

  102. Pantelyushin S, Haak S, Ingold B, Kulig P, Heppner FL, Navarini AA, Becher B (2012) Rorgammat+ innate lymphocytes and gammadelta T cells initiate psoriasiform plaque formation in mice. J Clin Invest 122:2252–2256

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Nakajima K, Terao M, Takaishi M, Kataoka S, Goto-Inoue N, Setou M, Horie K, Sakamoto F, Ito M, Azukizawa H, Kitaba S, Murota H, Itami S, Katayama I, Takeda J, Sano S (2013) Barrier abnormality due to ceramide deficiency leads to psoriasiform inflammation in a mouse model. J Invest Dermatol 133:2555–2565

    Article  CAS  PubMed  Google Scholar 

  104. Hayday AC (2000) [gamma][delta] cells: a right time and a right place for a conserved third way of protection. Annu Rev Immunol 18:975–1026

    Article  CAS  PubMed  Google Scholar 

  105. Thedrez A, Sabourin C, Gertner J, Devilder MC, Allain-Maillet S, Fournie JJ, Scotet E, Bonneville M (2007) Self/non-self discrimination by human gammadelta T cells: simple solutions for a complex issue? Immunol Rev 215:123–135

    Article  CAS  PubMed  Google Scholar 

  106. Deusch K, Luling F, Reich K, Classen M, Wagner H, Pfeffer K (1991) A major fraction of human intraepithelial lymphocytes simultaneously expresses the gamma/delta T cell receptor, the CD8 accessory molecule and preferentially uses the V delta 1 gene segment. Eur J Immunol 21:1053–1059

    Article  CAS  PubMed  Google Scholar 

  107. Groh V, Rhinehart R, Secrist H, Bauer S, Grabstein KH, Spies T (1999) Broad tumor-associated expression and recognition by tumor-derived gamma delta T cells of MICA and MICB. Proc Natl Acad Sci U S A 96:6879–6884

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Wu J, Groh V, Spies T (2002) T cell antigen receptor engagement and specificity in the recognition of stress-inducible MHC class I-related chains by human epithelial gamma delta T cells. J Immunol 169:1236–1240

    Article  CAS  PubMed  Google Scholar 

  109. Xu B, Pizarro JC, Holmes MA, McBeth C, Groh V, Spies T, Strong RK (2011) Crystal structure of a gammadelta T-cell receptor specific for the human MHC class I homolog MICA. Proc Natl Acad Sci U S A 108:2414–2419

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Russano AM, Bassotti G, Agea E, Bistoni O, Mazzocchi A, Morelli A, Porcelli SA, Spinozzi F (2007) CD1-restricted recognition of exogenous and self-lipid antigens by duodenal gammadelta+ T lymphocytes. J Immunol 178:3620–3626

    Article  CAS  PubMed  Google Scholar 

  111. Bai L, Picard D, Anderson B, Chaudhary V, Luoma A, Jabri B, Adams EJ, Savage PB, Bendelac A (2012) The majority of CD1d-sulfatide-specific T cells in human blood use a semiinvariant Vdelta1 TCR. Eur J Immunol 42:2505–2510

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Uldrich AP, Le Nours J, Pellicci DG, Gherardin NA, McPherson KG, Lim RT, Patel O, Beddoe T, Gras S, Rossjohn J, Godfrey DI (2013) CD1d-lipid antigen recognition by the gammadelta TCR. Nat Immunol 14:1137–1145

    Article  CAS  PubMed  Google Scholar 

  113. Luoma AM, Castro CD, Mayassi T, Bembinster LA, Bai L, Picard D, Anderson B, Scharf L, Kung JE, Sibener LV, Savage PB, Jabri B, Bendelac A, Adams EJ (2013) Crystal structure of Vdelta1 T cell receptor in complex with CD1d-sulfatide shows MHC-like recognition of a self-lipid by human gammadelta T cells. Immunity 39:1032–1042

    Article  CAS  PubMed  Google Scholar 

  114. Maeurer MJ, Martin D, Walter W, Liu K, Zitvogel L, Halusczcak K, Rabinowich H, Duquesnoy R, Storkus W, Lotze MT (1996) Human intestinal Vdelta1+ lymphocytes recognize tumor cells of epithelial origin. J Exp Med 183:1681–1696

    Article  CAS  PubMed  Google Scholar 

  115. Uyemura K, Ho CT, Ohmen JD, Rea TH, Modlin RL (1992) Selective expansion of V delta 1 + T cells from leprosy skin lesions. J Invest Dermatol 99:848–852

    Article  CAS  PubMed  Google Scholar 

  116. Dechanet J, Merville P, Lim A, Retiere C, Pitard V, Lafarge X, Michelson S, Meric C, Hallet MM, Kourilsky P, Potaux L, Bonneville M, Moreau JF (1999) Implication of gammadelta T cells in the human immune response to cytomegalovirus. J Clin Invest 103:1437–1449

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Vermijlen D, Brouwer M, Donner C, Liesnard C, Tackoen M, Van Rysselberge M, Twite N, Goldman M, Marchant A, Willems F (2010) Human cytomegalovirus elicits fetal gammadelta T cell responses in utero. J Exp Med 207:807–821

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Giacomelli R, Matucci-Cerinic M, Cipriani P, Ghersetich I, Lattanzio R, Pavan A, Pignone A, Cagnoni ML, Lotti T, Tonietti G (1998) Circulating Vdelta1+ T cells are activated and accumulate in the skin of systemic sclerosis patients. Arthritis Rheum 41:327–334

    Article  CAS  PubMed  Google Scholar 

  119. Morita CT, Jin C, Sarikonda G, Wang H (2007) Nonpeptide antigens, presentation mechanisms, and immunological memory of human Vgamma2Vdelta2 T cells: discriminating friend from foe through the recognition of prenyl pyrophosphate antigens. Immunol Rev 215:59–76

    Article  CAS  PubMed  Google Scholar 

  120. Vavassori S, Kumar A, Wan GS, Ramanjaneyulu GS, Cavallari M, El Daker S, Beddoe T, Theodossis A, Williams NK, Gostick E, Price DA, Soudamini DU, Voon KK, Olivo M, Rossjohn J, Mori L, De Libero G (2013) Butyrophilin 3A1 binds phosphorylated antigens and stimulates human gammadelta T cells. Nat Immunol 14:908–916

    Article  CAS  PubMed  Google Scholar 

  121. Sandstrom A, Peigne CM, Leger A, Crooks JE, Konczak F, Gesnel MC, Breathnach R, Bonneville M, Scotet E, Adams EJ (2014) The intracellular B30.2 domain of butyrophilin 3A1 binds phosphoantigens to mediate activation of human Vgamma9Vdelta2 T cells. Immunity 40:490–500

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Dieli F, Poccia F, Lipp M, Sireci G, Caccamo N, Di Sano C, Salerno A (2003) Differentiation of effector/memory Vdelta2 T cells and migratory routes in lymph nodes or inflammatory sites. J Exp Med 198:391–397

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. De Rosa SC, Andrus JP, Perfetto SP, Mantovani JJ, Herzenberg LA, Herzenberg LA, Roederer M (2004) Ontogeny of gamma delta T cells in humans. J Immunol 172:1637–1645

    Article  PubMed  Google Scholar 

  124. Parker CM, Groh V, Band H, Porcelli SA, Morita C, Fabbi M, Glass D, Strominger JL, Brenner MB (1990) Evidence for extrathymic changes in the T cell receptor gamma/delta repertoire. J Exp Med 171:1597–1612

    Article  CAS  PubMed  Google Scholar 

  125. Kabelitz D, He W (2012) The multifunctionality of human Vgamma9Vdelta2 gammadelta T cells: clonal plasticity or distinct subsets? Scand J Immunol 76:213–222

    Article  CAS  PubMed  Google Scholar 

  126. Caccamo N, Todaro M, Sireci G, Meraviglia S, Stassi G, Dieli F (2013) Mechanisms underlying lineage commitment and plasticity of human gammadelta T cells. Cell Mol Immunol 10:30–34

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Workalemahu G, Foerster M, Kroegel C, Braun RK (2003) Human gamma delta-T lymphocytes express and synthesize connective tissue growth factor: effect of IL-15 and TGF-beta 1 and comparison with alpha beta-T lymphocytes. J Immunol 170:153–157

    Article  CAS  PubMed  Google Scholar 

  128. Workalemahu G, Foerster M, Kroegel C (2004) Expression and synthesis of fibroblast growth factor-9 in human gammadelta T-lymphocytes. Response to isopentenyl pyrophosphate and TGF-beta1/IL-15. J Leukoc Biol 75:657–663

    Article  CAS  PubMed  Google Scholar 

  129. Ness-Schwickerath KJ, Jin C, Morita CT (2010) Cytokine requirements for the differentiation and expansion of IL-17A- and IL-22-producing human Vgamma2Vdelta2 T cells. J Immunol 184:7268–7280

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Moens E, Brouwer M, Dimova T, Goldman M, Willems F, Vermijlen D (2011) IL-23R and TCR signaling drives the generation of neonatal Vgamma9Vdelta2 T cells expressing high levels of cytotoxic mediators and producing IFN-gamma and IL-17. J Leukoc Biol 89:743–752

    Article  CAS  PubMed  Google Scholar 

  131. Caccamo N, La Mendola C, Orlando V, Meraviglia S, Todaro M, Stassi G, Sireci G, Fournie JJ, Dieli F (2011) Differentiation, phenotype, and function of interleukin-17-producing human Vgamma9Vdelta2 T cells. Blood 118:129–138

    Article  CAS  PubMed  Google Scholar 

  132. Maggi L, Santarlasci V, Capone M, Peired A, Frosali F, Crome SQ, Querci V, Fambrini M, Liotta F, Levings MK, Maggi E, Cosmi L, Romagnani S, Annunziato F (2010) CD161 is a marker of all human IL-17-producing T-cell subsets and is induced by RORC. Eur J Immunol 40:2174–2181

    Article  CAS  PubMed  Google Scholar 

  133. Laggner U, Di Meglio P, Perera GK, Hundhausen C, Lacy KE, Ali N, Smith CH, Hayday AC, Nickoloff BJ, Nestle FO (2011) Identification of a novel proinflammatory human skin-homing Vgamma9Vdelta2 T cell subset with a potential role in psoriasis. J Immunol 187:2783–2793

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Seung NR, Park EJ, Kim CW, Kim KH, Kim KJ, Cho HJ, Park HR (2007) Comparison of expression of heat-shock protein 60, Toll-like receptors 2 and 4, and T-cell receptor gammadelta in plaque and guttate psoriasis. J Cutan Pathol 34:903–911

    Article  PubMed  Google Scholar 

  135. Das H, Groh V, Kuijl C, Sugita M, Morita CT, Spies T, Bukowski JF (2001) MICA engagement by human Vgamma2Vdelta2 T cells enhances their antigen-dependent effector function. Immunity 15:83–93

    Article  CAS  PubMed  Google Scholar 

  136. Rincon-Orozco B, Kunzmann V, Wrobel P, Kabelitz D, Steinle A, Herrmann T (2005) Activation of V gamma 9V delta 2 T cells by NKG2D. J Immunol 175:2144–2151

    Article  CAS  PubMed  Google Scholar 

  137. Wrobel P, Shojaei H, Schittek B, Gieseler F, Wollenberg B, Kalthoff H, Kabelitz D, Wesch D (2007) Lysis of a broad range of epithelial tumour cells by human gamma delta T cells: involvement of NKG2D ligands and T-cell receptor- versus NKG2D-dependent recognition. Scand J Immunol 66:320–328

    Article  CAS  PubMed  Google Scholar 

  138. Lanca T, Correia DV, Moita CF, Raquel H, Neves-Costa A, Ferreira C, Ramalho JS, Barata JT, Moita LF, Gomes AQ, Silva-Santos B (2010) The MHC class Ib protein ULBP1 is a nonredundant determinant of leukemia/lymphoma susceptibility to gammadelta T-cell cytotoxicity. Blood 115:2407–2411

    Article  CAS  PubMed  Google Scholar 

  139. Alexander AA, Maniar A, Cummings JS, Hebbeler AM, Schulze DH, Gastman BR, Pauza CD, Strome SE, Chapoval AI (2008) Isopentenyl pyrophosphate-activated CD56+ {gamma}{delta} T lymphocytes display potent antitumor activity toward human squamous cell carcinoma. Clin Cancer Res 14:4232–4240

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Qin G, Liu Y, Zheng J, Xiang Z, Ng IH, Malik Peiris JS, Lau YL, Tu W (2012) Phenotypic and functional characterization of human gammadelta T-cell subsets in response to influenza A viruses. J Infect Dis 205:1646–1653

    Article  CAS  PubMed  Google Scholar 

  141. Fournie JJ, Sicard H, Poupot M, Bezombes C, Blanc A, Romagne F, Ysebaert L, Laurent G (2013) What lessons can be learned from gammadelta T cell-based cancer immunotherapy trials? Cell Mol Immunol 10:35–41

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Brandes M, Willimann K, Moser B (2005) Professional antigen-presentation function by human gammadelta T Cells. Science 309:264–268

    Article  CAS  PubMed  Google Scholar 

  143. Brandes M, Willimann K, Bioley G, Levy N, Eberl M, Luo M, Tampe R, Levy F, Romero P, Moser B (2009) Cross-presenting human gammadelta T cells induce robust CD8+ alphabeta T cell responses. Proc Natl Acad Sci U S A 106:2307–2312

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Cheng L, Cui Y, Shao H, Han G, Zhu L, Huang Y, O’Brien RL, Born WK, Kaplan HJ, Sun D (2008) Mouse gammadelta T cells are capable of expressing MHC class II molecules, and of functioning as antigen-presenting cells. J Neuroimmunol 203:3–11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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  1. Department of Dermatology, Kido Hospital, Niigata, Japan

    Kazuhiro Kawai

  2. Department of Dermatology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan

    Kazuhiro Kawai

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  1. Department of Dermatology, Kyoto University Grad Sch of Med., Sakyo-ku, Kyoto, Japan

    Kenji Kabashima

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Kawai, K. (2016). γδ T Cells. In: Kabashima, K. (eds) Immunology of the Skin. Springer, Tokyo. https://doi.org/10.1007/978-4-431-55855-2_6

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