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  • Review Article
  • Published:

γδ T cell effector functions: a blend of innate programming and acquired plasticity

Nature Reviews Immunology volume 10, pages 467–478 (2010)Cite this article

Subjects

Key Points

  • Effector functions of γδ T cells influence the outcome of the host responses to infections, injury and malignancy, and they have a role in the pathology of allergic and autoimmune diseases. Although γδ T cells share functional features with other cells of the immune system, specialization of γδ T cell subsets and the timing and tissue localization of their functional engagement makes their responses unique.

  • Effector functions of the γδ T cell subsets develop under the influence of innate programming and environmental signals. Programming during thymocyte maturation restricts the functional potential of populations of γδ T cells expressing given T cell receptors (TCRs) but they retain some degree of functional plasticity that is influenced by the context of an ongoing immune response.

  • The γδ T cells interact with a wide range of cell types, including innate immune cells, T cells and B cells, as well as non-immune tissue cells. Such interactions might trigger regulatory and cytotoxic responses of γδ T cells, they also induce innate and adaptive immunity, and they can promote tissue repair and wound healing.

  • Although studies in mice have been useful in identifying possible roles for γδ T cells in vivo, several differences between mouse and human subsets limit the translation of these findings to human γδ T cells. Nevertheless, comparison of functionally analogous subsets in both species is expected to provide insight into the immunobiology of human γδ T cells.

  • Clinical-grade compounds that mediate human γδ T cell activation have been shown to accelerate pathogen clearance and tissue repair in bacterial and viral infections, and such treatments correlate with disease stabilization or tumour regression in patients with malignancies.

  • A key remaining challenge for future study is the γδ TCR itself, of which the precise mode of action and role in the development and triggering of γδ T cell effector functions remains poorly understood.

Abstract

γδ T cells have several innate cell-like features that allow their early activation following recognition of conserved stress-induced ligands. Here we review recent observations revealing the ability of γδ T cells to rapidly produce cytokines that regulate pathogen clearance, inflammation and tissue homeostasis in response to tissue stress. These studies provide insights into how they acquire these properties, through both developmental programming in the thymus and functional polarization in the periphery. Innate features of γδ T cells underlie their non-redundant role in several physiopathological contexts and are therefore being exploited in the design of new immunotherapeutic approaches.

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Figure 1: Sensing of cellular stress and infection by γδ T cells.
Figure 2: Functional programming of invariant or invariant-like γδ T cell subsets.
Figure 3: Cellular interplay involving γδ T cells.
Figure 4: T cell–dendritic cell interactions in a normal mouse lung.

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References

  1. Janeway, C. A. & Medzhitov, R. Innate immune recognition. Annu. Rev. Immunol. 20, 197–216 (2002).

    Article  CAS  PubMed  Google Scholar 

  2. Gallucci, S., Lolkema, M. & Matzinger, P. Natural adjuvants: endogenous activators of dendritic cells. Nature Med. 5, 1249–1255 (1999).

    Article  CAS  PubMed  Google Scholar 

  3. Medzhitov, R. Origin and physiological roles of inflammation. Nature 454, 428–435 (2008).

    Article  CAS  PubMed  Google Scholar 

  4. Banchereau, J. & Steinman, R. M. Dendritic cells and the control of immunity. Nature 392, 245–252 (1998).

    Article  CAS  PubMed  Google Scholar 

  5. Bendelac, A., Bonneville, M. & Kearney, J. F. Autoreactivity by design: innate B and T lymphocytes. Nature Rev. Immunol. 1, 177–186 (2001).

    Article  CAS  Google Scholar 

  6. Treiner, E. et al. Selection of evolutionary conserved mucosal-associated invariant T cells by MR1. Nature 422, 164–169 (2003).

    Article  CAS  PubMed  Google Scholar 

  7. Hayday, A. C. γδ T cells and the lymphoid stress-surveillance response. Immunity 31, 184–196 (2009).

    Article  CAS  PubMed  Google Scholar 

  8. Chien, Y. H. & Konigshofer, Y. Antigen recognition by γδ T cells. Immunol. Rev. 215, 46–58 (2007).

    Article  CAS  PubMed  Google Scholar 

  9. Sciammas, R. et al. Unique antigen recognition by a herpesvirus-specific TCR γδ cell. J. Immunol. 152, 5392–5397 (1994).

    CAS  PubMed  Google Scholar 

  10. Scotet, E. et al. Tumor recognition following Vγ9Vδ2 T cell receptor interations with a surface F1-ATPase-related structure and apolipoprotein A-I. Immunity 22, 71–80 (2005).

    Article  CAS  PubMed  Google Scholar 

  11. Adams, E. J., Chien, Y. H. & Garcia, K. C. Structure of a γδ T cell receptor in complex with the nonclassical MHC T22. Science 308, 227–231 (2005). This paper details the first crystal structure of a γδ TCR in complex with its cognate ligand, revealing an unusual mode of molecular interaction compared with the docking of αβ TCRs on classical MHC molecules.

    Article  CAS  PubMed  Google Scholar 

  12. Aydintug, M. K., Roark, C. L., Chain, J. L., Born, W. K. & O'Brien, R. L. Macrophages express multiple ligands for γδ TCRs. Mol. Immunol. 45, 3253–3263 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Constant, P. et al. Stimulation of human γδ T cells by nonpeptidic mycobacterial antigens. Science 264, 267–270 (1994).

    Article  CAS  PubMed  Google Scholar 

  14. Tanaka, Y. et al. Natural and synthetic non-peptide antigens recognized by human γδ T cells. Nature 375, 155–158 (1995). References 13 and 14 provide early evidence for activation of human γδ T cells by non-peptide phosphorylated antigens of microbial or mammalian origins.

    Article  CAS  PubMed  Google Scholar 

  15. Hintz, M. et al. Identification of (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate as a major activator for human γδ T cells in Escherichia coli. FEBS Lett. 509, 317–322 (2001).

    Article  CAS  PubMed  Google Scholar 

  16. Halary, F. et al. Shared reactivity of Vδ2− γδ T cells against cytomegalovirus-infected cells and tumor intestinal epithelial cells. J. Exp. Med. 201, 1567–1578 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Thedrez, A. et al. Self/non-self discrimination by human γδ T cells: simple solutions for a complex issue? Immunol. Rev. 215, 123–135 (2007).

    Article  CAS  PubMed  Google Scholar 

  18. Raulet, D. H. & Guerra, N. Oncogenic stress sensed by the immune system: role of natural killer cell receptors. Nature Rev. Immunol. 9, 568–578 (2009).

    Article  CAS  Google Scholar 

  19. Viey, E. et al. Phosphostim-activated γδ T cells kill autologous metastatic renal cell carcinoma. J. Immunol. 174, 1338–1347 (2005).

    Article  CAS  PubMed  Google Scholar 

  20. Corvaisier, M. et al. Vγ9Vδ2 T cell response to colon carcinoma cells. J. Immunol. 175, 5481–5488 (2005).

    Article  CAS  PubMed  Google Scholar 

  21. Girardi, M. et al. Regulation of cutaneous malignancy by γδ T cells. Science 294, 605–609 (2001). This paper shows the first strong evidence for a crucial role of γδ T cells in tumour immunosurveillance.

    Article  CAS  PubMed  Google Scholar 

  22. Qin, G. et al. Phosphoantigen-expanded human γδ T cells display potent cytotoxicity against monocyte-derived macrophages infected with human and avian influenza viruses. J. Infect. Dis. 200, 858–865 (2009).

    Article  CAS  PubMed  Google Scholar 

  23. Strid, J. et al. Acute upregulation of an NKG2D ligand promotes rapid reorganization of a local immune compartment with pleiotropic effects on carcinogenesis. Nature Immunol. 9, 146–154 (2008).

    Article  CAS  Google Scholar 

  24. Shibata, K., Yamada, H., Hara, H., Kishihara, K. & Yoshikai, Y. Resident Vδ1+ γδ T cells control early infiltration of neutrophils after Escherichia coli infection via IL-17 production. J. Immunol. 178, 4466–4472 (2007).

    Article  CAS  PubMed  Google Scholar 

  25. Martin, B., Hirota, K., Cua, D. J., Stockinger, B. & Veldhoen, M. Interleukin-17 producing γδ T cells selectively expand in response to pathogen products and environmental signals. Immunity 31, 321–330 (2009).

    Article  CAS  PubMed  Google Scholar 

  26. Raulet, D. H. Interplay of natural killer cells and their receptors with the adaptive immune response. Nature Immunol. 5, 996–1002 (2004).

    Article  CAS  Google Scholar 

  27. Zitvogel, L., Terme, M., Borg, C. & Trinchieri, G. Dendritic cell-NK cross-talk: regulation and physiopathology. Curr. Top. Microbiol. Immunol. 298, 157–174 (2006).

    CAS  PubMed  Google Scholar 

  28. Brigl, M. & Brenner, M. B. CD1: antigen presentation and T cell function. Annu. Rev. Immunol. 22, 817–890 (2004).

    Article  CAS  PubMed  Google Scholar 

  29. Devilder, M.-C. et al. Potentiation of antigen-stimulated Vγ9Vδ2 T cell cytokine production by immature dendritic cells (DC) and reciprocal effect on DC maturation. J. Immunol. 176, 1386–1393 (2006).

    Article  CAS  PubMed  Google Scholar 

  30. Conti, L. et al. Reciprocal activating interactions between dendritic cells and pamidronate-stimulated γδ T cells: role of CD86 and inflammatory cytokines. J. Immunol. 174, 252–260 (2005).

    Article  CAS  PubMed  Google Scholar 

  31. Devilder, M. C., Allain, S., Dousset, C., Bonneville, M. & Scotet, E. Early triggering of exclusive IFN-γ responses of human Vγ9Vδ2 T cells by TLR-activated myeloid and plasmacytoid dendritic cells. J. Immunol. 183, 3625–3633 (2009).

    Article  CAS  PubMed  Google Scholar 

  32. Parker, C. M. et al. Evidence for extrathymic changes in the T cell receptor γδ repertoire. J. Exp. Med. 171, 1597–1612 (1990).

    Article  CAS  PubMed  Google Scholar 

  33. Adams, E. J., Strop, P., Shin, S., Chien, Y. H. & Garcia, K. C. An autonomous CDR3δ is sufficient for recognition of the nonclassical MHC class I molecules T10 and T22 by γδ T cells. Nature Immunol. 9, 777–784 (2008).

    Article  CAS  Google Scholar 

  34. Dieli, F. et al. Granulysin-dependent killing of intracellular and extracellular Mycobacterium tuberculosis by Vγ9/Vδ2 T lymphocytes. J. Infect. Dis. 184, 1082–1085 (2001).

    Article  CAS  PubMed  Google Scholar 

  35. Dudal, S. et al. Release of LL-37 by activated human Vγ9Vδ2 T cells: a microbicidal weapon against Brucella suis. J. Immunol. 177, 5533–5539 (2006).

    Article  CAS  PubMed  Google Scholar 

  36. Hamada, S. et al. IL-17A produced by γδ T cells plays a critical role in innate immunity against Listeria monocytogenes infection in the liver. J. Immunol. 181, 3456–3463 (2008).

    Article  CAS  PubMed  Google Scholar 

  37. Jameson, J. & Havran, W. L. Skin γδ T-cell functions in homeostasis and wound healing. Immunol. Rev. 215, 114–122 (2007).

    Article  CAS  PubMed  Google Scholar 

  38. O'Brien, R. L. et al. γδ T cell receptors: functional correlations. Immunol. Rev. 215, 77–88 (2007).

    Article  CAS  PubMed  Google Scholar 

  39. Simonian, P. L. et al. IL-17A-expressing T cells are essential for bacterial clearance in a murine model of hypersensitivity pneumonitis. J. Immunol. 182, 6540–6549 (2009). This study, as well as references 24 and 36, showed that γδ T cells are prominent sources of IL-17 during infection.

    Article  CAS  PubMed  Google Scholar 

  40. Gerber, D. J. et al. IL-4-producing γδ T cells that express a very restricted TCR repertoire are preferentially localized in liver and spleen. J. Immunol. 163, 3076–3082 (1999).

    CAS  PubMed  Google Scholar 

  41. Huber, S., Shi, C. & Budd, R. C. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Lahn, M. et al. MHC class I-dependent Vγ4+ pulmonary T cells regulate αβ T cell-independent airway responsiveness. Proc. Natl Acad. Sci. USA 99, 8850–8855 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Roark, C. L. et al. Exacerbation of collagen-induced arthritis by oligoclonal, IL-17-producing γδ T cells. J. Immunol. 179, 5576–5583 (2007).

    Article  CAS  PubMed  Google Scholar 

  44. Morita, C. T. et al. Functionally distinct subsets of human γδ T cells. Eur. J. Immunol. 21, 2999–3007 (1991).

    Article  CAS  PubMed  Google Scholar 

  45. Fenoglio, D. et al. γδ T lymphocytes producing IFN-γ and IL-17 are expanded in HIV-1-infected patients and respond to Candida albicans. Blood 113, 6611–6618 (2009).

    Article  CAS  PubMed  Google Scholar 

  46. Chen, L. et al. Epigenetic and transcriptional programs lead to default IFN-γ production by γδ T cells. J. Immunol. 178, 2730–2736 (2007).

    Article  CAS  PubMed  Google Scholar 

  47. Qi, Q. et al. Enhanced development of CD4+ γδ T cells in the absence of Itk results in elevated IgE production. Blood 114, 564–571 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. O'Brien, R. L., Roark, C. L. & Born, W. K. IL-17-producing γδ T cells. Eur. J. Immunol. 39, 662–666 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Kabelitz, D. & Wesch, D. Features and functions of γδ T lymphocytes: focus on chemokines and their receptors. Crit. Rev. Immunol. 23, 339–370 (2003).

    Article  CAS  PubMed  Google Scholar 

  50. Haas, J. D. et al. CCR6 and NK1.1 distinguish between IL-17A and IFN-γ-producing γδ effector T cells. Eur. J. Immunol. 39, 3488–3497 (2009).

    Article  CAS  PubMed  Google Scholar 

  51. Casetti, R. et al. Cutting edge: TGF-β1 and IL-15 induce FOXP3+ γδ regulatory T cells in the presence of antigen stimulation. J. Immunol. 183, 3574–3577 (2009).

    Article  CAS  PubMed  Google Scholar 

  52. Vermijlen, D. et al. Distinct cytokine-driven responses of activated blood γδ T cells: insights into unconventional T cell pleiotropy. J. Immunol. 178, 4304–4314 (2007).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  54. Lewis, J. et al. Selection of the cutaneous intraepithelial γδ T cell repertoire by a thymic stromal element. Nature Immunol. 7, 843–850 (2006).

    Article  CAS  Google Scholar 

  55. Xiong, N., Kang, C. & Raulet, D. H. Positive selection of dendritic epidermal γδ T cell precursors in the fetal thymus determines expression of skin-homing receptors. Immunity 21, 121–131 (2004).

    Article  CAS  PubMed  Google Scholar 

  56. Boyden, L. M. et al. Skint1, the prototype of a newly identified immunoglobulin superfamily gene cluster, positively selects epidermal γδ T cells. Nature Genet. 40, 656–662 (2008). References 54 to 56 suggest that the highly restricted TCR repertoire of skin γδ T cells results from a developmental programming induced by intrathymic positive selection.

    Article  CAS  PubMed  Google Scholar 

  57. Kreslavsky, T. et al. TCR-inducible PLZF transcription factor required for innate phenotype of a subset of γδ T cells with restricted TCR diversity. Proc. Natl Acad. Sci. USA 106, 12453–12458 (2009). This study provides strong evidence for molecular and developmental similarities between mouse invariant NKT cells and an NKT cell-like subset of γδ T cells with hepatosplenic tropism.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Kovalovsky, D. et al. The BTB-zinc finger transcriptional regulator PLZF controls the development of invariant natural killer T cell effector functions. Nature Immunol. 9, 1055–1064 (2008).

    Article  CAS  Google Scholar 

  59. Felices, M., Yin, C. C., Kosaka, Y., Kang, J. & Berg, L. J. Tec kinase Itk in γδ T cells is pivotal for controlling IgE production in vivo. Proc. Natl Acad. Sci. USA 106, 8308–8313 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Nunez-Cruz, S. et al. LAT regulates γδ T cell homeostasis and differentiation. Nature Immunol. 4, 999–1008 (2003).

    Article  CAS  Google Scholar 

  61. Parravicini, V., Field, A. C., Tomlinson, P. D., Basson, M. A. & Zamoyska, R. Itch−/− αβ and γδ T cells independently contribute to autoimmunity in Itchy mice. Blood 111, 4273–4282 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Jensen, K. D. C. et al. Thymic selection determines γδ T cell effector fate: antigen-naive cells make interleukin-17 and antigen-experienced cells make interferon γ. Immunity 29, 90–100 (2008). This study provides direct evidence that TCR–ligand interactions in the thymus can determine the potential of γδ T cells to produce certain cytokines.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Ribot, J. C. et al. CD27 is a thymic determinant of the balance between interferon-γ- and interleukin-17-producing γδ T cell subsets. Nature Immunol. 10, 427–436 (2009).

    Article  CAS  Google Scholar 

  64. Do, J.-S. et al. Cutting edge: spontaneous development of IL-17-producing γδ T cells in the thymus occurs via a TGF-β1-dependent mechanism. J. Immunol. 184, 1675–1679 (2010).

    Article  CAS  PubMed  Google Scholar 

  65. Romani, L. et al. Defective tryptophan catabolism underlies inflammation in mouse chronic granulomatous disease. Nature 451, 211–215 (2008).

    Article  CAS  PubMed  Google Scholar 

  66. Wesch, D., Glatzel, A. & Kabelitz, D. Differentiation of resting human peripheral blood γδ T cells toward Th1- or Th2-phenotype. Cell. Immunol. 212, 110–117 (2001).

    Article  CAS  PubMed  Google Scholar 

  67. Thedrez, A. et al. IL-21-mediated potentiation of antitumor cytolytic and proinflammatory responses of human Vγ9Vδ2 T cells for adoptive immunotherapy. J. Immunol. 182, 3423–3431 (2009).

    Article  CAS  PubMed  Google Scholar 

  68. Dobmeyer, T. S. et al. Reciprocal alterations of Th1/Th2 function in γδ T-cell subsets of human immunodeficiency virus-1-infected patients. Br. J. Haematol. 118, 282–288 (2002).

    Article  PubMed  Google Scholar 

  69. Li, B. et al. Disease-specific changes in γδ T cell repertoire and function in patients with pulmonary tuberculosis. J. Immunol. 157, 4222–4229 (1996).

    CAS  PubMed  Google Scholar 

  70. Rincon-Orozco, B. et al. Activation of Vγ9Vδ2 T cells by NKG2D. J. Immunol. 175, 2144–2151 (2005).

    Article  CAS  PubMed  Google Scholar 

  71. Jin, N. et al. Mismatched antigen prepares γδ T cells for suppression of airway hyperresponsiveness. J. Immunol. 174, 2671–2679 (2005).

    Article  CAS  PubMed  Google Scholar 

  72. Cook, L. et al. Evidence that CD8+ dendritic cells enable the development of γδ T cells that modulate airway hyperresponsiveness. J. Immunol. 181, 309–319 (2008).

    Article  CAS  PubMed  Google Scholar 

  73. Huang, Y. et al. The influence of IgE-enhancing and IgE-suppressive γδ T cell changes with exposure to inhaled ovalbumin. J. Immunol. 183, 849–855 (2009).

    Article  CAS  PubMed  Google Scholar 

  74. Duan, J., Chung, H., Troy, E. & Kasper, D. L. Microbial colonization drives expansion of IL-1 receptor 1-expressing and IL-17-producing γδ T cells. Cell Host Microbe 7, 140–150 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Peng, M. Y. et al. Interleukin 17-producing γδ T cells increased in patients with active pulmonary tuberculosis. Cell. Mol. Immunol. 5, 203–208 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  76. Stark, M. A. et al. Phagocytosis of apoptotic neutrophils regulates granulopoiesis via IL-23 and IL-17. Immunity 22, 285–294 (2005).

    Article  CAS  PubMed  Google Scholar 

  77. Braun, R. K. et al. IL-17 producing γδ T cells are required for a controlled inflammatory response after bleomycin-induced lung injury. Inflammation 31, 167–179 (2008).

    Article  CAS  PubMed  Google Scholar 

  78. Carding, S. R. et al. Late dominance of the inflammatory process in murine influenza by γδ T cells. J. Exp. Med. 172, 1225–1231 (1990).

    Article  CAS  PubMed  Google Scholar 

  79. Mombaerts, P., Arnoldi, J., Russ, F., Tonegawa, S. & Kaufmann, S. H. E. Different roles of αβ and γδ T cells in immunity against an intracellular bacterial pathogen. Nature 365, 53–56 (1993). This study provides the first strong evidence for a crucial anti-inflammatory role of mouse γδ T cells.

    Article  CAS  PubMed  Google Scholar 

  80. 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 

  81. Dalton, J. E., Howell, G., Pearson, J., Scott, P. & Carding, S. R. Fas–Fas ligand interactions are essential for the binding to and killing of activated macrophages by γδ T cells. J. Immunol. 173, 3660–3667 (2004). This study, and reference 65, provides strong evidence for a key role of IL-17-producing γδ T cells in several immunopathological processes.

    Article  CAS  PubMed  Google Scholar 

  82. Ito, Y. et al. γδ T cells are the predominant source of interleukin-17 in affected joints in collagen-induced arthritis, but not in rheumatoid arthritis. Arthritis Rheum. 60, 2294–2303 (2009).

    Article  CAS  PubMed  Google Scholar 

  83. Shichita, T. et al. Pivotal role of cerebral interleukin-17-producing γδ T cells in the delayed phase of ischemic brain injury. Nature Med. 15, 946–950 (2009).

    Article  CAS  PubMed  Google Scholar 

  84. Eberl, M. et al. A rapid crosstalk of human γδ T cells and monocytes drives the acute inflammation in bacterial infections. PLoS Pathog. 5, e1000308 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. Cui, Y. et al. Major role of γδ T cells in the generation of IL-17+ uveitogenic T cells. J. Immunol. 183, 560–567 (2009).

    Article  CAS  PubMed  Google Scholar 

  86. Brandes, M., Williman, K. & Moser, B. Professional antigen-presenting function by human γδ T cells. Science 309, 264–268 (2005).

    Article  CAS  PubMed  Google Scholar 

  87. Brandes, M. et al. Cross-presenting human γδ T cells induce robust CD8+ αβ T cell responses. Proc. Natl Acad. Sci. USA 106, 2307–2312 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Wu, Y. et al. Human γδ T cells: a lymphoid lineage capable of professional phagocytosis. J. Immunol. 183, 5622–5629 (2009).

    Article  CAS  PubMed  Google Scholar 

  89. Cheng, L. et al. Mouse γδ T cells are capable of expressing MHC class II molecules, and of functioning as antigen-presenting cells. J. Neuroimmunol. 203, 3–11 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Koizumi, H. et al. Expression of perforin and serine esterases by human γδ T cells. J. Exp. Med. 173, 499–502 (1991).

    Article  CAS  PubMed  Google Scholar 

  91. Mukasa, A., Lahn, M., Pflum, E. K., Born, W. & O' Brien, R. L. Evidence that the same γδ T cells respond during infection-induced and autoimmune inflammation. J. Immunol. 159, 5787–5794 (1997).

    CAS  PubMed  Google Scholar 

  92. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Bhagat, G. et al. Small intestinal CD8+ TCR γδ+ NKG2A+ intraepithelial lymphocytes have attributes of regulatory cells in patients with celiac disease. J. Clin. Invest. 118, 281–293 (2008).

    Article  CAS  PubMed  Google Scholar 

  94. Ashour, H. M. & Niederkorn, J. Y. γδ T cells promote anterior chamber-associated immune deviation and immune priviledge through their production of IL-10. J. Immunol. 177, 8331–8337 (2006).

    Article  CAS  PubMed  Google Scholar 

  95. Peng, G. et al. Tumor-infiltrating γδ T cells suppress T and dendritic cell function via mechanisms controlled by a unique Toll-like receptor signalling pathway. Immunity 27, 334–348 (2007).

    Article  CAS  PubMed  Google Scholar 

  96. Hahn, Y. S. et al. Vγ1+ γδ T cells reduce IL-10-producing CD4+CD25+ T cells in the lung of ovalbumin-sensitized and challenged mice. Immunol. Lett. 121, 87–92 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Wen, L. et al. Germinal center formation, immunoglobulin class switching, and autoantibody production driven by “non αβ” T cells. J. Exp. Med. 183, 2271–2282 (1996).

    Article  CAS  PubMed  Google Scholar 

  98. Pao, W. et al. γδ T cell help of B cells is induced by repeated parasitic infection, in the absence of other T cells. Curr. Biol. 6, 1317–1325 (1996).

    Article  CAS  PubMed  Google Scholar 

  99. Zuany-Amorim, C. et al. Requirement for γδ T cells in allergic airway inflammation. Science 280, 1265–1267 (1998).

    Article  CAS  PubMed  Google Scholar 

  100. McMenamin, C., Pimm, C., McKersey, M. & Holt, P. G. Regulation of IgE responses to inhaled antigen in mice by antigen-specific γδ T cells. Science 265, 1869–1871 (1994). This report was an early demonstration that mouse γδ T cells can regulate IgE responses.

    Article  CAS  PubMed  Google Scholar 

  101. Mizoguchi, A. et al. Role of the CD5 molecule on TCR γδ T cell-mediated immune functions: development of germinal centers and chronic intestinal inflammation. Int. Immunol. 15, 97–108 (2003).

    Article  CAS  PubMed  Google Scholar 

  102. Brandes, M. et al. Flexible migration program regulates γδ T-cell involvement in humoral immunity. Blood 102, 3693–3701 (2003).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Yang, H., Antony, P. A., Wildhaber, B. E. & Teitelbaum, D. H. Intestinal intraepithelial lymphocyte γδ-T cell-derived keratinocyte growth factor modulates epithelial growth in the mouse. J. Immunol. 172, 4151–4158 (2004).

    Article  CAS  PubMed  Google Scholar 

  105. Chen, Y., Chou, K., Fuchs, E., Havran, W. L. & Boismenu, R. Protection of the intestinal mucosa by intraepithelial γδ T cells. Proc. Natl Acad. Sci. USA 99, 14338–14343 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Inagaki-Ohara, K. et al. Mucosal T cells bearing TCR γδ play a protective role in intestinal inflammation. J. Immunol. 173, 1390–1398 (2004).

    Article  CAS  PubMed  Google Scholar 

  107. Tsuchiya, T. et al. Role of γδ T cells in the inflammatory response of experimental colitis mice. J. Immunol. 171, 5507–5513 (2003).

    Article  CAS  PubMed  Google Scholar 

  108. Inagaki-Ohara, K., Sawaguchi, A., Suganuma, T., Matsusaki, G. & Nawa, Y. Intraepithelial lymphocytes express junctional molecules in murine small intestine. Biochem. Biophys. Res. Comm. 331, 977–983 (2005).

    Article  CAS  PubMed  Google Scholar 

  109. Roberts, S. J. et al. T-cell 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Jameson, J. M., Cauvi, G., Witherden, D. A. & Havran, W. L. A keratinocyte-responsive γδ TCR is necessary for dendritic epidermal T cell activation by damaged keratinocytes and maintenance in the epidermis. J. Immunol. 172, 3573–3579 (2004).

    Article  CAS  PubMed  Google Scholar 

  111. Jameson, J. M., Cauvi, G., Sharp, L. L., Witherden, D. A. & Havran, W. L. γδ T cell-induced hyaluronan production by epithelial cells regulates inflammation. J. Exp. Med. 201, 1269–1279 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Toulon, A. et al. A role for human skin-resident T cells in wound healing. J. Exp. Med. 206, 743–750 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Li, Z., Burns, A. R., Rumbaut, R. E. & Smith, C. W. γδ T cells are necessary for platelet and neutrophil accumulation in limbal vessels and efficient epithelial repair after corneal abrasion. Am. J. Pathol. 171, 838–845 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. 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 

  115. Heyborne, K. D., Cranfill, R. L., Carding, S. R., Born, W. K. & O'Brien, R. L. Characterization of γδ T lymphocytes at the maternal-fetal interface. J. Immunol. 149, 2872–2878 (1992).

    CAS  PubMed  Google Scholar 

  116. Reardon, C. et al. Expression of γδ T cell receptors on lymphocytes from the lactating mammary gland. J. Exp. Med. 172, 1263–1266 (1990).

    Article  CAS  PubMed  Google Scholar 

  117. Miyazaki, K. et al. Gene expression profiling of peripheral T cell lymphoma including γδ T cell lymphoma. Blood 113, 1071–1074 (2008).

    Article  PubMed  CAS  Google Scholar 

  118. Bonneville, M. & Scotet, E. Human Vγ9Vδ2 T cells: promising new leads for immunotherapy of infections and tumors. Curr. Opin. Immunol. 18, 539–546 (2007).

    Article  CAS  Google Scholar 

  119. Sicard, H. et al. In vivo immunomanipulation of Vγ9Vδ2 T cells with a synthetic phosphoantigen in a preclinical nonhuman primate model. J. Immunol. 175, 5471–5480 (2005).

    Article  CAS  PubMed  Google Scholar 

  120. Huang, D. et al. Antigen-specific Vγ2Vδ2 T effector cells confer homeostatic protection against pneumonic plaque lesions. Proc. Natl Acad. Sci. USA 106, 7553–7558 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Wilhelm, M. et al. γδ T cells for immune therapy of patients with lymphoid malignancies. Blood 102, 200–206 (2003).

    Article  CAS  PubMed  Google Scholar 

  122. Dieli, F. et al. Targeting human γδ T cells with zoledronate and interleukin-2 for immunotherapy of hormone-refractory prostate cancer. Cancer Res. 67, 7450–7457 (2008).

    Article  CAS  Google Scholar 

  123. Zarski, J. P. et al. Repeated administration of IPH1101 in monotherapy or combined with low dose IL-2 in patients chronically infected with hepatitis C virus: efficacy, safety and immuno-biology results from a phase 2 study. Hepatology Abstr. 50, 1031A (2009).

    Google Scholar 

  124. Gertner-Dardenne, J. et al. Bromohydrin pyrophosphate enhances antibody-dependent cell-mediated cytotoxicity induced by therapeutic antibodies. Blood 113, 4875–4884 (2009).

    Article  CAS  PubMed  Google Scholar 

  125. Laurent, G. et al. Phase I/II study of IPH1101 (BrHPP), a Vγ9Vδ2 T cell agonist, combined with Rituximab in low grade follicular lymphoma patients — interim data. Blood Abstr. 114, 658A (2009).

    Google Scholar 

  126. Moreau, J. F. et al. Increases in CD3+CD4−CD8− T lymphocytes in AIDS patients with disseminated Mycobacterium avium-intracellulare complex infection. J. Infect. Dis. 174, 969–976 (1996).

    Article  CAS  PubMed  Google Scholar 

  127. Dechanet, J. et al. Implication of γδ T cells in the human immune response to cytomegalovirus. J. Clin. Invest. 103, 1437–1449 (1999). An early demonstration that distinct subsets of human γδ T cells respond to cytomegalovirus in vivo , and that these cells might have an important role in antiviral resistance in immunosuppressed renal transplant patients.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Tonegawa, S. et al. Diversity, development, ligands, and probable functions of γδ T cells. Cold Spring Harb. Symp. Quant. Biol. 54, 31–44 (1989).

    Article  CAS  PubMed  Google Scholar 

  129. Raulet, D. H. The structure, function and molecular genetics of the human γδ T cell receptor. Annu. Rev. Immunol. 7, 175–207 (1989).

    Article  CAS  PubMed  Google Scholar 

  130. Heilig, J. S. & Tonegawa, S. Diversity of murine γ genes and expression in fetal and adult T lymphocytes. Nature 322, 836–840 (1986).

    Article  CAS  PubMed  Google Scholar 

  131. Lefranc, M. P. & Rabbitts, T. H. A nomenclature to fit the organization of the human T-cell receptor γ and δ genes. Res. Immunol. 141, 615–618 (1990).

    Article  CAS  PubMed  Google Scholar 

  132. Mossmann, T. R. & Coffman, R. L. Th1 and Th2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu. Rev. Immunol. 7, 145–173 (1989).

    Article  Google Scholar 

  133. Dong, C. Th17 cells in development: an updated view of their molecular identity and genetic programming. Nature Rev. Immunol. 8, 337–348 (2008).

    Article  CAS  Google Scholar 

  134. King, C. New insights into the differentiation and function of T follicular helper cells. Nature Rev. Immunol. 9, 757–766 (2009).

    Article  CAS  Google Scholar 

  135. Huber, S. A., Graveline, D., Newell, M. K., Born, W. K. & O'Brien, R. L. Vγ1+ T cells suppress and Vγ4+ T cells promote susceptibility to coxsackievirus B3-induced myocarditis in mice. J. Immunol. 165, 4174–4181 (2000). The paper shows early evidence that functional roles of γδ T cell subsets correlate with their expressed TCRs.

    Article  CAS  PubMed  Google Scholar 

  136. Hahn, Y. S. et al. Different potentials of γδ T cell subsets in regulating airway responsiveness: Vγ1+ cells, but not Vγ4+ cells, promote airway hyperreactivity, TH2 cytokines, and airway inflammation. J. Immunol. 172, 2894–2902 (2004).

    Article  CAS  PubMed  Google Scholar 

  137. Matsubara, S. et al. Vγ1+ T cells and tumor necrosis factor-α in ozone-induced airway hyperresponsiveness. Am. J. Respir. Cell. Mol. Biol. 40, 454–463 (2009).

    Article  CAS  PubMed  Google Scholar 

  138. Jin, N. et al. Airway hyperresponsiveness through synergy of γδ T cells and NKT cells. J. Immunol. 179, 2961–2968 (2007).

    Article  CAS  PubMed  Google Scholar 

  139. Dodd, J., Riffault, S., Kodituwakku, J. S., Hayday, A. C. & Openshaw, P. J. Pulmonary Vγ4+ γδ T cells have proinflammatory and antiviral effects in viral lung disease. J. Immunol. 182, 1174–1181 (2009).

    Article  CAS  PubMed  Google Scholar 

  140. Welte, T. et al. Role of two distinct γδ T cell subsets during West Nile virus infection. FEMS Immunol. Med. Microbiol. 53, 275–283 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. 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).

    Article  CAS  PubMed  Google Scholar 

  142. Wu, H. et al. Depletion of γδ T cells exacerbates murine adriamycin nephropathy. J. Am. Soc. Nephrol. 18, 1180–1189 (2007).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank H. Sicard (Innate Pharma, Marseilles, France) for helpful suggestions, Z. Yin (Yale School of Medicine, New Haven, Connecticut, USA) for personal communication and J. M. Wands (NJH, Denver, Colorado, USA) for the image used in figure 4.

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  1. Institut National de la Sant et de la Recherche Mdicale (INSERM) U892, IRT UN, 8 quai Moncousu, BP 70721, 44007, Nantes cedex 1, France

    Marc Bonneville

  2. Integrated Department of Immunology, National Jewish Health and University of Colorado, Denver, 80206, Colorado, USA

    Rebecca L. O'Brien & Willi K. Born

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  1. Marc Bonneville
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Correspondence to Marc Bonneville or Willi K. Born.

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Marc Bonneville is a founder scientist of the company Innate Pharma, which has been developing immunotherapeutic approaches targeting γδ T cells. Some of such immunotherapeutic trials are mentioned in the Review.

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Glossary

Pattern recognition receptor

(PRR). A host receptor (such as Toll-like receptors (TLRs) or NOD-like receptors (NLRs)) that can sense pathogen-associated molecular patterns and initiate signalling cascades that lead to an innate immune response. These can be membrane bound (such as TLRs) or soluble cytoplasmic receptors (such as retinoic acid-inducible gene I (RIG-I), melanoma differentiation-associated gene 5 (MDA5) and NLRs).

Conventional αβ T cell

A T cell subset specific for peptide antigens that are presented by polymorphic MHC class I molecules (HLA-A, HLA-B, HLA-C in humans, H–2K, H–2D, H–2L in mice) or MHC class II molecules (HLA-DP, HLA-DQ, HLA-DR in humans, I–E or I–A in mice).

Invariant NKT cell

(iNKT cell). Lymphocytes that express a particular variable gene segment, Vα14 (in mice) and Vα24 (in humans), precisely rearranged to a particular Jα gene segment to yield T cell receptor α-chains with an invariant sequence. Typically, these cells express memory T cell markers and NK cell receptors, are enriched in the liver, are activated by recognition of CD1d (particularly when bound with α-galactosylceramide) and readily produce IL-2, IL-4, IL-13 and IFNγ.

Mucosa-associated invariant T cell

(MAIT cell). A conserved mammalian T cell subset expressing TCR α-chains with a canonical Vα7.2 junctional sequence in rodents and humans. MAIT cells are specific for an as yet undefined antigen that is bound to the monomorphic MHC class I-related MR1 product. Similar to iNKT cells, MAIT cells frequently express memory T cell markers and NK cell receptors, but differ from iNKT cells by their tropism for intestinal rather than liver tissues.

Pathogen-associated molecular pattern

(PAMP). Conserved motifs recognized by PRRs that are broadly expressed by various classes of microorganisms but absent from mammals. Examples include lipoteichoic acid (in Gram-positive bacteria), lipoarabinomannan (in mycobacteria), dextran (in fungi), lipopolysaccharide (in Gram-negative bacteria), double-stranded RNA (in viruses) and CpG DNA (in bacteria).

Danger-associated molecular pattern

(DAMP). A conserved mammalian motif, recognized by PRRs, that is broadly upregulated in response to cellular stress. Examples include heat shock proteins, high motility group box 1 protein (HMGB1), DNA-bending proteins and uric acid.

Natural killer receptors

(NKRs). Receptors initially identified on NK cells and later shown to be expressed by some memory T cells as well. NKRs are either related to immunoglobulins (such as killer immunoglobulin-like receptors (KIRs) or to C-type lectins (such as NKRP1 or CD94–NKG2). Some NKRs (such as the KIRS gene products) deliver activating signals whereas others (such as the MHC class I-specific KIRLl gene products) deliver inhibitory signals.

Natural killer group 2, member D

(NKG2D). An activating lectin-like receptor expressed by most NK cells, CD8+ αβ T cells and γδ T cells. NKG2D is specific for different MHC class I-related ligands that may be upregulated on activated, transformed or virus-infected cells, such as members of the retinoic acid early transcript 1 (RAE1) and cytomegalovirus UL16-binding protein (ULBP) families in rodents and humans, or the MHC class polypeptide-related sequence A (MICA) and MICB in humans.

NOD-like receptors

(NLRs). A family of cytoplasmic PRRs that trigger immune responses against microbial threats. For example, NLRP3 senses microbial ligands, endogenous danger signals and certain crystalline substances, and it initiates the assembly of the NLRP3 inflammasome. 22 human and 34 mouse NLR genes have been identified.

Chronic granulomatous disease

(CGD). A human primary immunodeficiency syndrome associated with hyperinflammation and increased susceptibility to bacterial and fungal infections.

Allergic airway hyperresponsiveness

(Allergic AHR; also known as bronchial hyperresponsiveness). A state characterized by easily triggered bronchospasm (contraction of the small airways). AHR is a hallmark of asthma, and it occurs frequently in individuals with chronic obstructive pulmonary disease. It can be induced in mice by allergen sensitization and challenge or by airway exposure to environmental triggers such as ozone. Bronchial challenge with nonspecific agents such as methacholine or histamine is used as a test for AHR.

Antibody-dependent cell cytotoxicity

(ADCC). A cytotoxic mechanism mediated by engagement of low-affinity receptors for the constant fragment of IgG (FcγRIII; also known as CD16) by antibody-coated target cells.

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Bonneville, M., O'Brien, R. & Born, W. γδ T cell effector functions: a blend of innate programming and acquired plasticity. Nat Rev Immunol 10, 467–478 (2010). https://doi.org/10.1038/nri2781

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