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  • Review Article
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Regulatory lymphocytes

Immunoregulation in the tissues by γδ T cells

Key Points

  • γδ T-cell deficits are more often associated with defective immunoregulation than with a failure of immunity.

  • γδ T cells are disproportionately enriched in epithelia, and in certain strains of mice, γδ T-cell deficiency is associated with a spontaneous pathology that resembles human atopic dermatitis.

  • In terms of many of their features and properties, γδ T cells resemble other unconventional T cells, including subsets of αβ T cells. Defects in these cells also lead to dysregulation and immunopathology.

  • The regulation that is exerted by γδ T cells occurs at the effector stage in the tissues, rather than at the primary stage in the lymph nodes. Because of this, unconventional T-cell activity has potential importance for the amelioration of organ-specific autoimmune disease.

  • Immunoregulatory γδ T-cell subsets have several effector potentials, including the potential for cytolysis and chemokine secretion.

  • Immunoregulation by γδ T cells is under genetic control.

Abstract

For a T-cell subset to be classified as immunoregulatory, it might reasonably be predicted that in its absence, animals would experience pathological immune dysregulation. Moreover, reconstitution of the subset should restore normal immune regulation. So far, these criteria have been satisfied by only a few of the candidate regulatory T-cell subsets, but among them is the intraepithelial γδ T-cell receptor (TCR)+ subset of mouse skin. In this article, we look at immunoregulatory γδ T cells, and the growing evidence for tissue-associated immunoregulation mediated by both γδ T cells and αβ T cells.

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Figure 1: Almost all DETCs in the epidermis of normal mice express an invariant Vγ5Vδ1 T-cell receptor.
Figure 2: Adoptive transfer of Vγ5+ fetal thymocytes, but not of Vγ5 γδ lymph-node cells, restores a normal phenotype to susceptible FVB/N TCRδ-deficient mice.
Figure 3: Spontaneous dermatitis in genetically susceptible TCRδ-deficient mice depends on the environment.
Figure 4: Many mechanisms are available to γδ T cells to mediate local immunoregulation.

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References

  1. Hayday, A. C. γδ cells: a right time and a right place for a conserved third way of protection. Annu. Rev. Immunol. 18, 975–1026 (2000).

    CAS  PubMed  Google Scholar 

  2. Tonegawa, S. Somatic generation of antibody diversity. Nature 302, 575–581 (1983).

    Article  CAS  PubMed  Google Scholar 

  3. Shen, Y. et al. Adaptive immune response of Vγ2Vδ2+ T cells during mycobacterial infections. Science 295, 2255–2258 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. King, D. P. et al. Protective response to pulmonary injury requires γδ T lymphocytes. J. Immunol. 162, 5033–5036 (1999).

    CAS  PubMed  Google Scholar 

  5. Hiromatsu, K. et al. A protective role of γδ T cells in primary infection with Listeria monocytogenes in mice. J. Exp. Med. 175, 49–56 (1992).

    CAS  PubMed  Google Scholar 

  6. Skeen, M. J. & Ziegler, H. K. Induction of murine peritoneal γδ T cells and their role in resistance to bacterial infection. J. Exp. Med. 178, 971–984 (1993).

    CAS  PubMed  Google Scholar 

  7. Selin, L. K., Santolucito, P. A., Pinto, A. K., Szomolanyi-Tsuda, E. & Welsh, R. M. Innate immunity to viruses: control of vaccinia virus infection by γδ T cells. J. Immunol. 166, 6784–6794 (2001).

    CAS  PubMed  Google Scholar 

  8. Langhorne, J., Mombaerts, P. & Tonegawa, S. αβ and γδ T cells in the immune response to the erythrocytic stages of malaria in mice. Int. Immunol. 7, 1005–1111 (1995).

    CAS  PubMed  Google Scholar 

  9. Boismenu, R. & Havran, W. An innate view of γδ T cells. Curr. Opin. Immunol. 9, 57–63 (1997).

    CAS  PubMed  Google Scholar 

  10. Tanaka, Y., Morita, C., Nieves, E., Brenner, M. B. & Bloom, B. R. Natural and synthetic non-peptide antigens recognized by human γδ T cells. Nature 375, 155–158 (1995).

    CAS  PubMed  Google Scholar 

  11. Constant, P. et al. Stimulation of human γδ T cells by nonpeptidic mycobacterial ligands. Science 264, 267–270 (1994). The prototype paper introducing the concept of new, low-molecular-mass ligands for T cells.

    CAS  PubMed  Google Scholar 

  12. Chien, Y. H., Jores, R. & Crowley, M. P. Recognition by γδ T cells. Annu. Rev. Immunol. 14, 511–532 (1996).

    CAS  PubMed  Google Scholar 

  13. Crowley, M. P. et al. A population of murine γδ T cells that recognize an inducible MHC class Ib molecule. Science 287, 314–316 (2000). This study provides strong biochemical evidence for the recognition of thymus leukaemia antigen (TL)-type (class IB MHC) molecules by the γδ T-cell receptor.

    CAS  PubMed  Google Scholar 

  14. Tsujimura, K. et al. The binding of thymus leukaemia (TL) antigen tetramers to normal intestinal intraepithelial lymphocytes and thymocytes. J. Immunol. 167, 759–764 (2001).

    CAS  PubMed  Google Scholar 

  15. Janeway, C. A. et al. Specificity and function of cells bearing γδ T-cell receptors. Immunol. Today 9, 73–76 (1988).

    PubMed  Google Scholar 

  16. Steele, C. R., Oppenheim, D. E. & Hayday, A. C. γδ T cells: non-classical ligands for non-classical cells. Curr. Biol. 10, R282–R285 (2000).

    CAS  PubMed  Google Scholar 

  17. Groh, B., Steinle, A., Bauer, S. & Spies, T. Recognition of stress-induced MHC molecules by intestinal epithelial γδ T cells. Science 279, 1737–1740 (1998).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  19. Correa, I. et al. Most γδ T cells develop normally in β2-microglobulin-deficient mice. Proc. Natl Acad. Sci. USA 89, 653–657 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Das, G. & Janeway, C. A. Jr. Development of CD8αα and CD8αβ T cells in major histocompatibility complex class-I-deficient mice. J. Exp. Med. 190, 881–884 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Bucy, P., Chen, C. L., Cihak, J., Losch, U. & Cooper, M. Avian T cells expressing γδ receptors localize in the splenic sinusoids and the intestinal epithelium. J. Immunol. 141, 2200–2205 (1988).

    CAS  PubMed  Google Scholar 

  22. Stingl, G. et al. Thy-1+ dendritic epidermal cells express T3 antigen and the T-cell receptor γ-chain. Proc. Natl Acad. Sci. USA 84, 4586–4590 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Asarnow, D. et al. Limited diversity of γδ antigen-receptor genes of Thy-1+ dendritic epidermal cells. Cell 55, 837–847 (1988). The prototype paper introducing the concept of a monomorphic T-cell repertoire associated with a specific tissue.

    CAS  PubMed  Google Scholar 

  24. Goodman, T. & Lefrancois, L. Expression of the γδ T-cell receptor on intestinal CD8+ intraepithelial lymphocytes. Nature 333, 855–858 (1988).

    CAS  PubMed  Google Scholar 

  25. Kyes, S., Carew, E., Carding, S. R., Janeway, C. A. & Hayday, A. Diversity in T-cell receptor γ gene usage in intestinal epithelium. Proc. Natl Acad. Sci. USA 86, 5527–5531 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Itohara, S. et al. Homing of a γδ thymocyte subset with homogeneous T-cell receptors to mucosal epithelia. Nature 343, 754–757 (1990).

    CAS  PubMed  Google Scholar 

  27. Hayday, A. & Viney, J. L. The ins and outs of body-surface immunology. Science 290, 97–100 (2000).

    CAS  PubMed  Google Scholar 

  28. Allison, J. P. & Havran, W. L. The immunobiology of T cells with invariant γδ antigen receptors. Annu. Rev. Immunol. 9, 679–705 (1991).

    CAS  PubMed  Google Scholar 

  29. Haas, W. γδ cells. Annu. Rev. Immunol. 11, 637–685 (1993).

    CAS  PubMed  Google Scholar 

  30. Havran, W. L. & Allison, J. P. Developmentally ordered appearance of thymocytes expressing different T-cell antigen receptors. Nature 335, 443–445 (1988).

    CAS  PubMed  Google Scholar 

  31. McVay, L. D., Jaswal, S. S., Kennedy, C., Hayday, A. & Carding, S. The generation of human γδ T-cell repertoires during fetal development. J. Immunol. 160, 5851–5860 (1998).

    CAS  PubMed  Google Scholar 

  32. Lantz, O. & Bendelac, A. An invariant T-cell receptor α-chain is used by a unique subset of major histocompatibility complex class-I-specific CD4+ and CD48 T cells in mice and humans. J. Exp. Med. 180, 1097–1106 (1994).

    CAS  PubMed  Google Scholar 

  33. Bendelac, A. Positive selection of mouse NK1.1+ T cells by CD1-expressing cortical thymocytes. J. Exp. Med. 182, 2091–2096 (1995).

    Article  CAS  PubMed  Google Scholar 

  34. Tilloy, F. et al. An invariant T-cell receptor α-chain defines a novel TAP-independent major histocompatibility complex class-Ib-restricted αβ T-cell subpopulation in mammals. J. Exp. Med. 189, 1907–1921 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Lefrancois, L. Phenotypic complexity of intraepithelial lymphocytes of the small intestine. J. Immunol. 147, 1746–1751 (1991).

    CAS  PubMed  Google Scholar 

  36. Arstila, T. et al. Identical T-cell clones are located within the mouse gut epithelium and lamina propria and circulate in the thoracic duct lymph. J. Exp. Med. 191, 823–834 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Hayday, A., Theodoridis, E., Ramsburg, E. & Shires, J. Intraepithelial lymphocytes: exploring the Third Way in immunology. Nature Immunol. 2, 997–1003 (2001).

    CAS  Google Scholar 

  38. Havran, W., Chien, Y. & Allison, J. Recognition of self-antigens by skin-derived T cells with invariant γδ antigen receptors. Science 252, 1430–1432 (1991).

    CAS  PubMed  Google Scholar 

  39. Girardi, M. et al. Regulation of cutaneous malignancy by γδ T cells. Science 294, 605–609 (2001).

    CAS  PubMed  Google Scholar 

  40. Rocha, B., von Boehmer, H. & Guy-Grand, D. Selection of intraepithelial lymphocytes with CD8αα co-receptors by self-antigen in the murine gut. Proc. Natl Acad. Sci. USA 89, 5336–5340 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Lin, T. et al. Autospecific γδ thymocytes that escape negative selection find sanctuary in the intestine. J. Clin. Invest. 104, 1297–1305 (1999). An interesting paper providing evidence that gut-associated γδ T cells are positively selected in the thymus.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Urdahl, K. B., Sun, J. C. & Bevan, M. J. Positive selection of MHC class-Ib-restricted CD8+ T cells on hematopoietic cells. Nature Immunol. 3, 772–779 (2002).

    CAS  Google Scholar 

  43. Tsujimura, K. T. et al. Positive selection of γδ CTL by TL antigen expressed in the thymus. J. Exp. Med. 184, 2175–2184 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Mallick-Wood, C. A. et al. Conservation of T-cell receptor conformation in epidermal γδ cells with disrupted primary Vγ gene usage. Science 279, 1729–1733 (1998).

    CAS  PubMed  Google Scholar 

  45. Ferrero, I., Wilson, A., Beermann, F., Held, W. & MacDonald, H. R. T-cell receptor specificity is critical for the development of epidermal γδ T cells. J. Exp. Med. 194, 1473–1483 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Waters, W. R. & Harp, J. A. Cryptosporidium parvum infection in T-cell receptor (TCR)-α and TCR-δ deficient mice. Infect. Immun. 64, 1854–1857 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Smith, A. & Hayday, A. An αβ T-cell-independent immunoprotective response toward gut coccidia is supported by γδ cells. Immunology 101, 325–332 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Born, W. et al. Immunoregulatory functions of γδ T cells. Adv. Immunol. 71, 77–144 (1999).

    CAS  PubMed  Google Scholar 

  49. Mombaerts, P., Arnoldi, J., Russ, F., Tonegawa, S. & Kaufmann, S. H. Different roles of αβ and γδ T cells in immunity against an intracellular bacterial pathogen. Nature 365, 53–56 (1993).

    CAS  PubMed  Google Scholar 

  50. Fu, Y. X. et al. Immune protection and control of inflammatory tissue necrosis by γδ T cells. J. Immunol. 153, 3101–3115 (1994).

    CAS  PubMed  Google Scholar 

  51. D'Souza, C. D. et al. An anti-inflammatory role for γδ T cells in acquired immunity to Mycobacterium tuberculosis. J. Immunol. 158, 1217–1221 (1997). A good example of how defects in γδ T cells affect the form, but not the overall outcome, of the immune response that develops to a naturally administered pathogen.

    CAS  PubMed  Google Scholar 

  52. Mukasa, A. et al. Bacterial infection of the testis leading to autoaggressive immunity triggers apparently opposed responses of αβ and γδ T cells. J. Immunol. 155, 2047–2056 (1995). A thorough paper showing that the defects in γδ T-cell-deficient mice are evident as overt inflammation, whereas the main consequence of a defect in αβ T cells is failure to control infection.

    CAS  PubMed  Google Scholar 

  53. Mukasa, A., Born, W. & O'Brien, R. L. Inflammation alone evokes the response of a TCR-invariant mouse γδ T-cell subset. J. Immunol. 162, 4910–4913 (1999).

    CAS  PubMed  Google Scholar 

  54. Peng, S., Madaio, M., Hayday, A. C. & Craft, J. Propagation and regulation of systemic autoimmunity by γδ T cells. J. Immunol. 157, 5689–5698 (1996).

    CAS  PubMed  Google Scholar 

  55. Wen, L. et al. Immunoglobulin synthesis and generalised autoimmunity in mice congenitally deficient in αβ T cells. Nature 369, 654–658 (1994).

    CAS  PubMed  Google Scholar 

  56. Horner, A. A., Jabara, H., Ramesh, N. & Geha, R. S. γδ T lymphocytes express CD40 ligand and induce isotype switching in B lymphocytes. J. Exp. Med. 181, 1239–1244 (1995).

    CAS  PubMed  Google Scholar 

  57. Pao, W. et al. γδ T-cell help for B cells is stimulated by repeated parasitic infection. Curr. Biol. 6, 1317–1325 (1996).

    CAS  PubMed  Google Scholar 

  58. King, D. P. et al. Cutting edge: protective response to pulmonary injury requires γδ T lymphocytes. J. Immunol. 162, 5033–5036 (1999).

    CAS  PubMed  Google Scholar 

  59. Ladel, C. H., Blum, C. & Kaufmann, S. H. E. Control of natural killer cell-mediated innate resistance against the intracellular pathogen Listeria monocytogenes by γδ T lymphocytes. Infect. Immun. 64, 1744–1749 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Huber, S., Graveline, D., Newell, M., Born, W. & O'Brien, R. Vγ1+ T cells suppress and Vγ4+ T cells promote susceptibility to coxsackievirus B3-induced myocarditis in mice. J. Immunol. 165, 4174–4181 (2000). This study provides evidence that the outcome of immunoregulation by γδ T cells can be complex, with both pro- and anti-inflammatory consequences, depending on which γδ T-cell subsets are dominant.

    CAS  PubMed  Google Scholar 

  61. Huber, S., Sartini, D. & Exley, M. Vγ4+ T cells promote autoimmune CD8+ cytolytic T-lymphocyte activation in coxsackievirus B3-induced myocarditis in mice: role for CD4+ TH1 cells. J. Virol. 76, 10785–10790 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Hoyne, G. F., Dallman, M. J. & Lamb, J. R. T-cell regulation of peripheral tolerance and immunity: the potential role for Notch signalling. Immunology 100, 281–288 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Smith, A. L. & Hayday, A. C. Genetic dissection of primary and secondary responses to a widespread natural pathogen of the gut, Eimeria vermiformis. Infect. Immun. 68, 6273–6280 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Roberts, S. et al. T-cell receptor αβ+ and γδ+ deficient mice display abnormal but distinct phenotypes toward a natural, widespread infection of the intestinal epithelium. Proc. Natl Acad. Sci. USA 93, 11774–11779 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Shiohara, T. et al. Loss of epidermal integrity by T-cell-mediated attack induces long-term local resistance to subsequent attack. I. Induction of resistance correlates with increases in Thy1+ epidermal-cell numbers. J. Exp. Med. 171, 1027–1041 (1990).

    CAS  PubMed  Google Scholar 

  66. Shiohara, T., Moriya, N., Hayakawa, J., Itohara, S. & Ishikawa, H. Resistance to cutaneous graft-vs.-host disease is not induced in T-cell receptor δ gene-mutant mice. J. Exp. Med. 183, 1483–1489 (1996). This study implicates skin-associated γδ T cells in regulating infiltration into the epidermis of a line of autoreactive αβ T cells.

    CAS  PubMed  Google Scholar 

  67. Girardi, M. et al. Resident skin-specific γδ T cells provide local, nonredundant regulation of cutaneous inflammation. J. Exp. Med. 195, 855–867 (2002). This study provides evidence that mice deficient for γδ T cells show a spontaneous loss of regulation of αβ T-cell responses in the skin.

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Mihm, M. C., Soter, N. A., Dvorak, H. F. & Austen, J. F. The structure of normal skin and the morphology of atopic eczema. J. Invest. Dermatol. 67, 305–312 (1976).

    PubMed  Google Scholar 

  69. Leung, D. Y. M., Bhan, A. K., Schneeberger, E. E. & Geha, R. S. Characterization of the mononuclear-cell infiltrate in atopic dermatitis using monoclonal antibodies. J. Allergy Clin. Immunol. 71, 47–56 (1983).

    CAS  PubMed  Google Scholar 

  70. Chamlin, S. L. et al. Ceramide-dominant barrier repair lipids alleviate childhood atopic dermatitis: changes in barrier function provide a sensitive indicator of disease activity. J. Am. Acad. Dermatol. 47, 198–208 (2002).

    PubMed  Google Scholar 

  71. Hanifin, J. M. & Raika, G. Diagnostic features of atopic dermatitis. Acta Dermatol. Venereol. (Stockholm) 92, 44–47 (1980).

    Google Scholar 

  72. Forrest, S. et al. Identifying genes predisposing to atopic eczema. J. Allergy Clin. Immunol. 104, 1066–1070 (1999).

    CAS  PubMed  Google Scholar 

  73. Cookson, W. O. et al. Genetic linkage of childhood atopic dermatitis to psoriasis-susceptibility loci. Nature Genet. 27, 372–373 (2001).

    CAS  PubMed  Google Scholar 

  74. Poussier, P., Ning, T., Banerjee, D. & Julius, M. A unique subset of self-specific intraintestinal T cells maintains gut integrity. J. Exp. Med. 195, 1491–1497 (2002). A clear demonstration that gut-associated unconventional αβ T cells downregulate systemic αβ T-cell-mediated inflammation in the tissues.

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Gonzalez, A., Andre-Schmutz, I., Carnaud, C., Mathis, D. & Benoist, C. Damage control rather than unresponsiveness effected by protective Dx5+ T cells in autoimmune diabetes. Nature Immunol. 2, 1117–1125 (2001). An intriguing example of tissue-associated immune regulation of αβ T-cell responses by a subset of αβ T cells expressing a natural killer-cell marker.

    CAS  Google Scholar 

  76. Fahrer, A. et al. Attributes of γδ intraepithelial lymphocytes as suggested by their transcriptional profile. Proc. Natl Acad. Sci. USA 98, 10261–10266 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Shires, J., Theodoridis, E. & Hayday, A. Biological insights into TCRγδ+ and TCRαβ+ intraepithelial lymphocytes provided by serial analysis of gene expression (SAGE). Immunity 15, 419–434 (2001).

    CAS  PubMed  Google Scholar 

  78. Bauer, S. et al. Activation of NK cells and T cells by NKG2d, a receptor for stress-inducible MICA. Science 285, 727–729 (1999).

    CAS  PubMed  Google Scholar 

  79. Ogasawara, K. et al. Impairment of NK-cell function by NKG2D modulation in NOD mice. Immunity 18, 41–51 (2003).

    CAS  PubMed  Google Scholar 

  80. Egan, P. & Carding, S. Downmodulation of the inflammatory response to bacterial infection by γδ T cells cytotoxic for activated macrophages. J. Exp. Med. 191, 2145–2158 (2000). A provocative mechanistic explanation for how γδ T cells might suppress the inflammatory response to a bacterial infection.

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Vincent, M. S. et al. Apoptosis of Fashigh CD4+ synovial T cells by Borrelia-reactive Fas-ligandhigh γδ T cells in Lyme arthritis. J. Exp. Med. 184, 2109–2117 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Huber, S., Shi, C. & Budd, R. γδ T cells promote a TH1 response during coxsackievirus B3 infection in vivo: role of Fas and Fas ligand. J. Virol. 76, 6487–6494 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Huber, S., Graveline, D., Born, W. & O'Brien, R. Cytokine production by Vγ+-T-cell subsets is an important factor determining CD4+-TH-cell phenotype and susceptibility of BALB/c mice to coxsackievirus B3-induced myocarditis. J. Virol. 75, 5860–5869 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Wen, L. et al. Primary γδ-cell clones can be defined phenotypically and functionally as TH1/TH2 cells and illustrate the association of CD4 with TH2 differentiation. J. Immunol. 160, 1965–1974 (1998).

    CAS  PubMed  Google Scholar 

  85. Yin, Z. et al. T-bet expression and failure of GATA-3 cross-regulation lead to default production of IFN-γ by γδ T cells. J. Immunol. 168, 1566–1571 (2002).

    CAS  PubMed  Google Scholar 

  86. Zelenika, D. et al. The role of CD4+ T-cell subsets in determining transplantation rejection or tolerance. Immunol. Rev. 182, 164–179 (2001).

    CAS  PubMed  Google Scholar 

  87. Young, J. D. et al. Thymosin β4 sulfoxide is an anti-inflammatory agent generated by monocytes in the presence of glucocorticoids. Nature Med. 5, 1424–1427 (1999).

    CAS  PubMed  Google Scholar 

  88. Rudin, C. M., Engler, P. & Storb, U. Differential splicing of thymosin β4 mRNA. J. Immunol. 144, 4857–4862 (1990).

    CAS  PubMed  Google Scholar 

  89. Jameson, J. et al. A role for skin γδ T cells in wound repair. Science 296, 747–749 (2002).

    CAS  PubMed  Google Scholar 

  90. Komano, H. et al. Homeostatic regulation of intestinal epithelia by intraepithelial γδ T cells. Proc. Natl Acad. Sci. USA 92, 6147–6151 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Hampe, J. et al. Association between insertion mutation in NOD2 gene and Crohn's disease in German and British populations. Lancet 357, 1925–1928 (2001).

    CAS  PubMed  Google Scholar 

  92. van Houten, N. & Huber, S. A. Genetics of coxsackie virus B3 (CVB3) myocarditis. Eur. Heart J. 12, 108–112 (1991).

    PubMed  Google Scholar 

  93. Sugita, M. & Brenner, M. B. T-lymphocyte recognition of human group 1 CD1 molecules: implications for innate and acquired immunity. Semin. Immunol. 12, 511–516 (2000).

    CAS  PubMed  Google Scholar 

  94. Jiang, H. & Chess, L. The specific regulation of immune responses by CD8+ T cells restricted by the MHC class Ib molecule, Qa-1. Annu. Rev. Immunol. 18, 185–216 (2000).

    CAS  PubMed  Google Scholar 

  95. Sakaguchi, S., Fukuma, K., Kuribayashi, K. & Masuda, T. Organ-specific autoimmune diseases induced in mice by elimination of a T-cell subset. I. Evidence for the active participation of T cells in natural self-tolerance; deficit of a T-cell subset as a possible cause of autoimmune disease. J. Exp. Med. 161, 72–87 (1985).

    CAS  PubMed  Google Scholar 

  96. Moore, T. A., Moore, B. B., Newstead, M. W. & Standiford, T. J. γδ T cells are critical for survival and early proinflammatory gene expression during murine Klebsiella pneumonia. J. Immunol. 165, 2643–2650 (2000).

    CAS  PubMed  Google Scholar 

  97. Nam, J. L., Lewis, J., Girardi, M. & Tigelaar, R. E. Genetic analysis of spontaneous dermatitis in γδ T-cell-deficient mice. J. Invest. Dermatol. 119, 301 (2002).

    Google Scholar 

  98. Girardi, M. et al. Anti-inflammatory effects in the skin of thymosin-β4 splice-variants. Immunology (in the press).

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Acknowledgements

We thank M. Girardi, our main collaborator in this work, and J. Lewis, J. Shires, M. Tigelaar and S. Creighton. We acknowledge support from the Wellcome Trust and the Yale Skin Diseases Research Center (National Institutes of Health).

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Correspondence to Adrian Hayday.

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DATABASES

Entrez

Eimeria

Listeria monocytogenes

Mycobacterium tuberculosis

LocusLink

β2m

BY55

CCL3

CCL4

CCL5

CD4

CD8α

CD25

CD45

CD95

CD95L

granzyme A

granzyme B

H2-M3

IFN-γ

IL-4

IL-10

LAG3

lymphotoxin

MICA

RAE1

Rag2

Stat4

Stat6

Tβ4

TCRα

TCRδ

ULBP

XCL1

Glossary

DENDRITIC EPIDERMAL T CELLS

(DETCs). γδ T-cell receptor (TCR)+ cells localized in the epidermis that are present in rodents and cattle, but not in humans. In mice, essentially all DETCs express precisely the same TCR, forming a prototype lymphocyte repertoire of limited diversity.

MRL/LPR MICE

A strain of mice that spontaneously develop glomerular nephritis and other symptoms of systemic lupus erythematosus ('lupus'). The lpr mutation causes a defect in Fas, preventing the apoptosis of activated lymphocytes; the MRL strain contributes disease-associated mutations that have yet to be identified.

MYOCARDITIS

An inflammatory disease of the heart that can be induced by various microbial and viral infections. The acute form of the disease seldom leads to lasting damage, but the chronic form can lead to fatal cardiomyopathy. A considerable part of the pathology seems to be a direct result of dysregulated activities of T helper 1 cells and CD8+ cytotoxic T lymphocytes.

FVB/N

An inbred mouse strain that is increasingly favoured for analyses because of its vigorous reproductive performance and consistently large litters. Fertilized FVB/N eggs contain large and prominent pronuclei, which facilitates microinjection of DNA and efficient transgenesis.

NON-OBESE DIABETIC

(NOD). A mouse strain that normally develops idiopathic autoimmune diabetes that closely resembles type 1 diabetes in humans. The target antigen(s) that is recognized by the pathogenic CD4+ T cells that initiate disease is expressed by pancreatic islet cells, but its identity has remained elusive.

ATOPIC DERMATITIS

A chronic skin disease in which the skin becomes extremely itchy and inflamed, causing redness, swelling, cracking, weeping, crusting and scaling. Its multifactorial pathogenesis involves genetic susceptibility, environmental triggers and immune dysregulation (typically dominated by T helper 2 cells), with the involvement of immunoglobulin E contributing to its classification as an atopic disease.

SEVERE COMBINED IMMUNODEFICIENCY

Mice of this phenotype lack functional T and B cells owing to a spontaneous mutation in the Prkdc gene (protein kinase, DNA activated, catalytic polypeptide) located on chromosome 16. These mice are often used for the reconstitution of T-cell subsets to study their functions in vivo in the absence of any other lymphocyte subsets.

FAS LIGAND–FAS

A pair of ligand–receptor molecules of the tumour-necrosis factor (TNF)–TNF-receptor family, the engagement of which usually induces apoptosis of the FAS-expressing cell. So, this is a mode of cytolysis effected by FASL+ cells.

ADOPTIVE TRANSFER

An experimental method in which lymphocytes from an antigen-primed donor mouse are introduced into a recipient mouse that lacks lymphocyte function.

PSORIASIS

A chronic skin disease affecting 1–2% of the population, in which the skin becomes inflamed, producing red, thickened areas with silvery scales, most often on the scalp, elbows, knees and lower back. Recent evidence points to a T-cell-mediated pathogenesis in genetically susceptible individuals, resulting in inflammation and epidermal hyperplasia.

CROHN DISEASE

Together with ulcerative colitis, Crohn disease is one of the two main forms of chronic inflammatory bowel disease (IBD). It most commonly affects the lower portion of the small intestine, resulting in symptoms of abdominal pain, diarrhoea, fever and weight loss. Analysis of the strong genetic predisposition led to the identification of mutations in the Nod2 gene that are particularly strongly associated with ileal disease, but not with ulcerative colitis.

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Hayday, A., Tigelaar, R. Immunoregulation in the tissues by γδ T cells. Nat Rev Immunol 3, 233–242 (2003). https://doi.org/10.1038/nri1030

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