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  • Review Article
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Six-of-the-best: unique contributions of γδ T cells to immunology

Key Points

  • Six properties may collectively distinguish γδ T cells from αβ T cells, and thereby define their unique contributions to lymphocyte biology.

  • One, γδ T cell receptors (TCRs) recognize a broad set of antigens. Although only a few γδ TCR ligands have been identified so far, they belong to diverse families of exogenous molecules and autoantigens (such as self or non-self proteins, lipids and phosphorylated isoprenoids), which underlines the capacity of these cells to respond to both foreign pathogens and stressed self.

  • Two, γδ T cells are rapid responders. γδ T cells, which mature in the thymus, do not require further peripheral maturation or extensive clonal expansion to initiate terminal effector functions. In addition to their diversified and localized distribution, they are well suited to provide a first line of defence in many tissues. The diversity of the antigen receptors that they express provides them with the potential to sense a greater variety of insults than can be sensed by dendritic cells.

  • Three, γδ T cells are developmentally pre-programmed. Unlike conventional αβ T cells, many γδ T cells acquire their functional effector phenotypes during development in the thymus, thereby facilitating fast responsiveness. Some functions, such as antigen presentation, are not functions associated with conventional αβ T cells. Recent developments point to specific molecular networks that drive pre-programming and that are strongly influenced by the strength of TCR signalling.

  • Four, γδ T cells predominantly reside in specific tissues. This distribution may originate via the selective expression of specific chemokine receptors, but the retention of these cells in tissues may reflect a steady-state engagement of tissue-specific ligands by particular pairs of TCR variable regions.

  • Five, γδ T cells have a broad contribution to immune responses. The large range of soluble factors produced by γδ T cells, and their potential to interact with and regulate most of the major immune cell subsets, are consistent with emerging evidence that γδ T cells have a key central role in many aspects of immunobiology and immunopathology.

  • Six, γδ T cells mediate crucial responses to specific pathogens. γδ T cells seem to be specialized in the defence of the host against a specific set of pathogens, including cytomegalovirus, Mycobacterium tuberculosis and Plasmodium falciparum. This might supplement the short-comings of conventional adaptive immune cells, particularly during early life.

Abstract

γδ T cells are a unique and conserved population of lymphocytes that have been the subject of a recent explosion of interest owing to their essential contributions to many types of immune response and immunopathology. But what does the integration of recent and long-established studies really tell us about these cells and their place in immunology? The time is ripe to consider the evidence for their unique and crucial functions. We conclude that whereas B cells and αβ T cells are commonly thought to contribute primarily to the antigen-specific effector and memory phases of immunity, γδ T cells are distinct in that they combine conventional adaptive features (inherent in their T cell receptors and pleiotropic effector functions) with rapid, innate-like responses that can place them in the initiation phase of immune reactions. This underpins a revised perspective on lymphocyte biology and the regulation of immunogenicity.

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Figure 1: An overview of prenatal and postnatal γδ T cell development.
Figure 2: An alternative way to achieve broad systemic immune responses.
Figure 3: Six of the best γδ T cell functions.

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References

  1. Kazen, A. R. & Adams, E. J. Evolution of the V, D, and J gene segments used in the primate γδ T-cell receptor reveals a dichotomy of conservation and diversity. Proc. Natl Acad. Sci. USA 108, E332–E340 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Dudley, E. C., Girardi, M., Owen, M. J. & Hayday, A. C. αβ and γδ T cells can share a late common precursor. Curr. Biol. 5, 659–669 (1995).

    Article  CAS  PubMed  Google Scholar 

  3. Boehm, T. et al. VLR-based adaptive immunity. Annu. Rev. Immunol. 30, 203–220 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Bucy, R. P., Chen, C. L., Cihak, J., Losch, U. & Cooper, M. D. 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 

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

    Article  CAS  PubMed  Google Scholar 

  6. Asarnow, D. M. et al. Limited diversity of γδ antigen receptor genes of Thy-1+ dendritic epidermal cells. Cell 55, 837–847 (1988).

    Article  CAS  PubMed  Google Scholar 

  7. Zeng, X. et al. γδ T cells recognize a microbial encoded B cell antigen to initiate a rapid antigen-specific interleukin-17 response. Immunity 37, 524–534 (2012). This work describes a new antigen for large numbers of both human and mouse γδ T cells and also demonstrates that functional responses driven by cytokines depend only on a pre-activation state triggered by TCR engagement.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Hogg, A. E., Worth, A., Beverley, P., Howard, C. J. & Villarreal-Ramos, B. The antigen-specific memory CD8+ T-cell response induced by BCG in cattle resides in the CD8+γ/δTCRCD45RO+ T-cell population. Vaccine 27, 270–279 (2009).

    Article  CAS  PubMed  Google Scholar 

  9. Huang, D. et al. Clonal immune responses of Mycobacterium-specific γδ T cells in tuberculous and non-tuberculous tissues during M. tuberculosis infection. PLoS ONE 7, e30631 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Plattner, B. L., Huffman, E. L. & Hostetter, J. M. γδ T-cell responses during subcutaneous Mycobacterium avium subspecies paratuberculosis challenge in sensitized or naive calves using matrix biopolymers. Vet. Pathol. 9 Oct 2012 (doi:10.1177/0300985812463404).

    Article  PubMed  CAS  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  13. Janeway, C. A. Jr., Jones, B. & Hayday, A. Specificity and function of T cells bearing γδ receptors. Immunol. Today 9, 73–76 (1988).

    Article  PubMed  Google Scholar 

  14. Crowley, M. P., Reich, Z., Mavaddat, N., Altman, J. D. & Chien, Y. The recognition of the nonclassical major histocompatibility complex (MHC) class I molecule, T10, by the γδ T cell, G8. J. Exp. Med. 185, 1223–1230 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Shin, S. et al. Antigen recognition determinants of γδ T cell receptors. Science 308, 252–255 (2005).

    Article  CAS  PubMed  Google Scholar 

  16. Matis, L. A. et al. Structure and specificity of a class II MHC alloreactive γδ T cell receptor heterodimer. Science 245, 746–749 (1989).

    Article  CAS  PubMed  Google Scholar 

  17. Xu, B. et al. Crystal structure of a γδ T-cell receptor specific for the human MHC class I homolog MICA. Proc. Natl Acad. Sci. USA 108, 2414–2419 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Kong, Y. et al. The NKG2D ligand ULBP4 binds to TCR γ9/δ2 and induces cytotoxicity to tumor cells through both TCRγδ and NKG2D. Blood 114, 310–317 (2009).

    Article  CAS  PubMed  Google Scholar 

  19. Willcox, C. R. et al. Cytomegalovirus and tumor stress surveillance by binding of a human γδ T cell antigen receptor to endothelial protein C receptor. Nature Immunol. 13, 872–879 (2012). This paper provides a biochemical basis for the functional cross-reactivity of a human γδ TCR towards virus-infected cells (foreign) and tumour cells (self).

    Article  CAS  Google Scholar 

  20. Spada, F. M. et al. Self-recognition of CD1 by γ/δ T cells: implications for innate immunity. J. Exp. Med. 191, 937–948 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Bai, L. et al. The majority of CD1d–sulfatide-specific T cells in human blood use a semiinvariant Vδ1 TCR. Eur. J. Immunol. 42, 2505–2510 (2012). This paper illustrates how γδ and αβ T cells can both focus on a single specificity, suggesting the integrated activity of the two T cell lineages in immunoprotection and in clinically relevant immunopathology, in this case multiple sclerosis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Zhang, L. et al. γδ T cell receptors confer autonomous responsiveness to the insulin-peptide B:9-23. J. Autoimmun. 34, 478–484 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Morita, C. T., Jin, C., Sarikonda, G. & Wang, H. Nonpeptide antigens, presentation mechanisms, and immunological memory of human Vγ2Vδ2 T cells: discriminating friend from foe through the recognition of prenyl pyrophosphate antigens. Immunol. Rev. 215, 59–76 (2007).

    Article  CAS  PubMed  Google Scholar 

  24. Morita, C. T. et al. Direct presentation of nonpeptide prenyl pyrophosphate antigens to human γδ T cells. Immunity 3, 495–507 (1995).

    Article  CAS  PubMed  Google Scholar 

  25. Eberl, M. & Moser, B. Monocytes and γδ T cells: close encounters in microbial infection. Trends Immunol. 30, 562–568 (2009).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  27. Mookerjee-Basu, J. et al. F1-adenosine triphosphatase displays properties characteristic of an antigen presentation molecule for Vγ9Vδ2 T cells. J. Immunol. 184, 6920–6928 (2010).

    Article  CAS  PubMed  Google Scholar 

  28. Vantourout, P. et al. Specific requirements for Vγ9Vδ2 T cell stimulation by a natural adenylated phosphoantigen. J. Immunol. 183, 3848–3857 (2009).

    Article  CAS  PubMed  Google Scholar 

  29. Monkkonen, H. et al. A new endogenous ATP analog (ApppI) inhibits the mitochondrial adenine nucleotide translocase (ANT) and is responsible for the apoptosis induced by nitrogen-containing bisphosphonates. Br. J. Pharmacol. 147, 437–445 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Bruder, J. et al. Target specificity of an autoreactive pathogenic human γδ-T cell receptor in myositis. J. Biol. Chem. 287, 20986–20995 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Raben, N. et al. A motif in human histidyl-transfer-RNA synthetase which is shared among several aminoacyl-transfer-RNA synthetases is a coiled-coil that is essential for enzymatic-activity and contains the major autoantigenic epitope. J. Biol. Chem. 269, 24277–24283 (1994).

    CAS  PubMed  Google Scholar 

  32. Harly, C. et al. Key implication of CD277/butyrophilin-3 (BTN3A) in cellular stress sensing by a major human γδ T-cell subset. Blood 120, 2269–2279 (2012). This paper describes the most recent development in our understanding of the complex mechanism governing phosphoantigen recognition by human Vγ9Vδ2+ T cells. CD277 is closely related to SKINT1, which was previously described as a crucial component in the intrathymic selection of mouse Vγ5Vδ1+ T cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Palakodeti, A. et al. The molecular basis for modulation of human Vγ9Vδ2 T cell responses by CD277/butyrophilin-3 (BTN3A)-specific antibodies. J. Biol. Chem. 287, 32780–32790 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. 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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  36. Davey, M. S. et al. Human neutrophil clearance of bacterial pathogens triggers anti-microbial γδ T cell responses in early infection. PLoS Pathog. 7, e1002040 (2011). This paper describes a pathophysiological role for γδ T cells by linking the activation of human γδ T cells by phosphoantigens to the handling of discrete classes of clinically relevant bacteria by neutrophils.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Gober, H. J. et al. Human T cell receptor γδ cells recognize endogenous mevalonate metabolites in tumor cells. J. Exp. Med. 197, 163–168 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Kistowska, M. et al. Dysregulation of the host mevalonate pathway during early bacterial infection activates human TCR γδ cells. Eur. J. Immunol. 38, 2200–2209 (2008).

    Article  CAS  PubMed  Google Scholar 

  39. Born, W. K. et al. Hybridomas expressing γδ T-cell receptors respond to cardiolipin and β2-glycoprotein 1 (apolipoprotein H). Scand. J. Immunol. 58, 374–381 (2003).

    Article  CAS  PubMed  Google Scholar 

  40. Baumgarth, N. The double life of a B-1 cell: self-reactivity selects for protective effector functions. Nature Rev. Immunol. 11, 34–46 (2011).

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  42. Swamy, M., Jamora, C., Havran, W. & Hayday, A. Epithelial decision makers: in search of the 'epimmunome'. Nature Immunol. 11, 656–665 (2010).

    Article  CAS  Google Scholar 

  43. Groh, V., Wu, J., Yee, C. & Spies, T. Tumour-derived soluble MIC ligands impair expression of NKG2D and T-cell activation. Nature 419, 734–738 (2002).

    Article  CAS  PubMed  Google Scholar 

  44. Lodoen, M. B. & Lanier, L. L. Viral modulation of NK cell immunity. Nature Rev. Microbiol. 3, 59–69 (2005).

    Article  CAS  Google Scholar 

  45. O'Brien, R. L. & Born, W. Heat shock proteins as antigens for γδ T cells. Semin. Immunol. 3, 81–87 (1991).

    CAS  PubMed  Google Scholar 

  46. Komori, H. K. et al. Cutting edge: dendritic epidermal γδ T cell ligands are rapidly and locally expressed by keratinocytes following cutaneous wounding. J. Immunol. 188, 2972–2976 (2012).

    Article  CAS  PubMed  Google Scholar 

  47. 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 

  48. Chodaczek, G., Papanna, V., Zal, M. A. & Zal, T. Body-barrier surveillance by epidermal γδ TCRs. Nature Immunol. 13, 272–282 (2012). This study used an elegant experimental approach for the visualization of epidermal Vγ5Vδ1+ T cells to show that their TCRs constantly engage ligands and signal, which seemingly contrasts with the hypothesis that a stress-induced antigen is required for γδ T cell activation.

    Article  CAS  Google Scholar 

  49. Taveirne, S. et al. Inhibitory receptors specific for MHC class I educate murine NK cells but not CD8αα intestinal intraepithelial T lymphocytes. Blood 118, 339–347 (2011).

    Article  CAS  PubMed  Google Scholar 

  50. Witherden, D. A. et al. The junctional adhesion molecule JAML is a costimulatory receptor for epithelial γδ T cell activation. Science 329, 1205–1210 (2010). This paper illustrates how IELs are regulated by a member of the JAM family, which has a fundamental role in the structural integrity of epithelial tissue. Hence, IELs are truly integrated into the tissue.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Witherden, D. A. et al. The CD100 receptor interacts with its plexin B2 ligand to regulate epidermal γδ T cell function. Immunity 37, 314–325 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Holl, E. K. et al. Plexin-B2 and Plexin-D1 in dendritic cells: expression and IL-12/IL-23p40 production. PLoS ONE 7, e43333 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Li, Y. et al. Exogenous stimuli maintain intraepithelial lymphocytes via aryl hydrocarbon receptor activation. Cell 147, 629–640 (2011).

    CAS  PubMed  Google Scholar 

  54. Veldhoen, M. et al. The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins. Nature 453, 106–109 (2008).

    Article  CAS  PubMed  Google Scholar 

  55. Kadow, S. et al. Aryl hydrocarbon receptor is critical for homeostasis of invariant γδ T cells in the murine epidermis. J. Immunol. 187, 3104–3110 (2011).

    Article  CAS  PubMed  Google Scholar 

  56. Fernandez-Salguero, P. et al. Immune system impairment and hepatic fibrosis in mice lacking the dioxin-binding Ah receptor. Science 268, 722–726 (1995).

    Article  CAS  PubMed  Google Scholar 

  57. Cardone, J. et al. Complement regulator CD46 temporally regulates cytokine production by conventional and unconventional T cells. Nature Immunol. 11, 862–871 (2010).

    Article  CAS  Google Scholar 

  58. 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 

  59. Strid, J., Sobolev, O., Zafirova, B., Polic, B. & Hayday, A. The intraepithelial T cell response to NKG2D-ligands links lymphoid stress surveillance to atopy. Science 334, 1293–1297 (2011). This thorough study using an inducible NKG2D ligand transgenic model demonstrated the lymphoid stress-surveillance capacity of mouse Vγ5Vδ1+ T cells and their potential to broadly regulate downstream systemic responses, solely in response to stress antigens and in the absence of microbial contribution.

    Article  CAS  PubMed  Google Scholar 

  60. Sharp, L. L., Jameson, J. M., Cauvi, G. & Havran, W. L. Dendritic epidermal T cells regulate skin homeostasis through local production of insulin-like growth factor 1. Nature Immunol. 6, 73–79 (2005).

    Article  CAS  Google Scholar 

  61. Motomura, Y. et al. The transcription factor E4BP4 regulates the production of IL-10 and IL-13 in CD4+ T cells. Nature Immunol. 12, 450–459 (2011).

    Article  CAS  Google Scholar 

  62. 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 

  63. Ansel, K. M. et al. A chemokine-driven positive feedback loop organizes lymphoid follicles. Nature 406, 309–314 (2000).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  65. Ehl, S. et al. A variant of SCID with specific immune responses and predominance of γδ T cells. J. Clin. Invest. 115, 3140–3148 (2005). This paper elegantly highlights how studies of selective human immunodeficiencies can inform us about the functional potentials of γδ T cells in vivo , such as the provision of B cell help.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Gil, J. et al. A leaky mutation in CD3D differentially affects αβ and γδ T cells and leads to a TαβTγδ+B+NK+ human SCID. J. Clin. Invest. 121, 3872–3876 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Caccamo, N. et al. CXCR5 identifies a subset of Vγ9Vδ2 T cells which secrete IL-4 and IL-10 and help B cells for antibody production. J. Immunol. 177, 5290–5295 (2006).

    CAS  PubMed  Google Scholar 

  68. Caccamo, N. et al. IL-21 regulates the differentiation of a human γδ T cell subset equipped with B cell helper activity. PLoS ONE 7, e41940 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Conti, L. et al. Reciprocal activating interaction 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 

  70. 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 

  71. Caccamo, N. et al. γδ T cells condition dendritic cells in vivo for priming pulmonary CD8 T cell responses against Mycobacterium tuberculosis. Eur. J. Immunol. 36, 2681–2690 (2006).

    Article  CAS  PubMed  Google Scholar 

  72. Lanzavecchia, A. Antigen-specific interaction between T and B cells. Nature 314, 537–539 (1985).

    Article  CAS  PubMed  Google Scholar 

  73. Brandes, M., Willimann, K. & Moser, B. Professional antigen-presentation function by human γδ T cells. Science 309, 264–268 (2005). This was the first study to clearly report the capacity of human Vγ9Vδ2+ T cells to present antigens to other T cells. Follow-up studies by this group and others have demonstrated that this capacity extends to antigen cross-presentation with efficiencies similar to those of professional antigen-presenting cells.

    Article  CAS  PubMed  Google Scholar 

  74. 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 

  75. Himoudi, N. et al. Human γδ T lymphocytes are licensed for professional antigen presentation by interaction with opsonized target cells. J. Immunol. 188, 1708–1716 (2012).

    Article  CAS  PubMed  Google Scholar 

  76. Roberts, N. A. et al. Rank signaling links the development of invariant γδ T cell progenitors and Aire+ medullary epithelium. Immunity 36, 427–437 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Bhagat, G. et al. Small intestinal CD8+TCRγδ+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 

  78. Hayday, A. & Tigelaar, R. Immunoregulation in the tissues by γδ T cells. Nature Rev. Immunol. 3, 233–242 (2003).

    Article  CAS  Google Scholar 

  79. Lahn, M. et al. γδ T cells as regulators of airway hyperresponsiveness. Int. Arch. Allergy Immunol. 125, 203–210 (2001).

    Article  CAS  PubMed  Google Scholar 

  80. Jin, Y. et al. Cutting edge: intrinsic programming of thymic γδT cells for specific peripheral tissue localization. J. Immunol. 185, 7156–7160 (2010).

    Article  CAS  PubMed  Google Scholar 

  81. Kyes, S., Pao, W. & Hayday, A. Influence of site of expression on the fetal γδ T-cell receptor repertoire. Proc. Natl Acad. Sci. USA 88, 7830–7833 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Jensen, K. D. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Turchinovich, G. & Hayday, A. C. Skint-1 identifies a common molecular mechanism for the development of interferon-γ-secreting versus interleukin-17-secreting γδ T cells. Immunity 35, 59–68 (2011). This study thoroughly dissects the developmental programme of mouse Vγ5Vδ1+ T cells, providing detailed molecular pathways and new insights into the development of pre-programmed γδ T cells in general.

    Article  CAS  PubMed  Google Scholar 

  84. 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 

  85. Verykokakis, M. et al. Inhibitor of DNA binding 3 limits development of murine Slam-associated adaptor protein-dependent “innate” γδ T cells. PLoS ONE 5, e9303 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Powolny-Budnicka, I. et al. RelA and RelB transcription factors in distinct thymocyte populations control lymphotoxin-dependent interleukin-17 production in γδ T cells. Immunity 34, 364–374 (2011). This study is a compelling illustration of how γδ T cell development is regulated not just by thymic epithelial cells but also by other thymocytes.

    Article  CAS  PubMed  Google Scholar 

  87. Silva-Santos, B., Pennington, D. J. & Hayday, A. C. Lymphotoxin-mediated regulation of γδ cell differentiation by αβ T cell progenitors. Science 307, 925–928 (2005).

    Article  CAS  PubMed  Google Scholar 

  88. Turchinovich, G. & Pennington, D. J. T cell receptor signalling in γδ cell development: strength isn't everything. Trends Immunol. 32, 567–573 (2011).

    Article  CAS  PubMed  Google Scholar 

  89. Kisielow, J., Tortola, L., Weber, J., Karjalainen, K. & Kopf, M. Evidence for the divergence of innate and adaptive T-cell precursors before commitment to the αβ and γδ lineages. Blood 118, 6591–6600 (2011).

    Article  CAS  PubMed  Google Scholar 

  90. Narayan, K. et al. Intrathymic programming of effector fates in three molecularly distinct γδ T cell subtypes. Nature Immunol. 13, 511–518 (2012).

    Article  CAS  Google Scholar 

  91. Michel, M. L. et al. Interleukin 7 (IL-7) selectively promotes mouse and human IL-17-producing γδ cells. Proc. Natl Acad. Sci. USA 109, 17549–17554 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Ness-Schwickerath, K. J., Jin, C. & Morita, C. T. Cytokine requirements for the differentiation and expansion of IL-17A- and IL-22-producing human Vγ2Vδ2 T cells. J. Immunol. 184, 7268–7280 (2010).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  94. Schulz, C. et al. A lineage of myeloid cells independent of Myb and hematopoietic stem cells. Science 336, 86–90 (2012).

    Article  CAS  PubMed  Google Scholar 

  95. De Rosa, S. C. et al. Ontogeny of γδ T cells in humans. J. Immunol. 172, 1637–1645 (2004).

    Article  CAS  PubMed  Google Scholar 

  96. Gibbons, D. L. et al. Neonates harbour highly active γδ T cells with selective impairments in preterm infants. Eur. J. Immunol. 39, 1794–1806 (2009).

    Article  CAS  PubMed  Google Scholar 

  97. Vermijlen, D. et al. Human cytomegalovirus elicits fetal γδ T cell responses in utero. J. Exp. Med. 207, 807–821 (2010). This paper demonstrates a fine example of the major role of γδ T cells in immunity to CMV, which may exert a major selective pressure for the retention of certain γδ T cell subsets, particularly in newborns.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Ramsburg, E., Tigelaar, R., Craft, J. & Hayday, A. Age-dependent requirement for γδ T cells in the primary but not secondary protective immune response against an intestinal parasite. J. Exp. Med. 198, 1403–1414 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Waters, W. R. et al. Cryptosporidium parvum-induced inflammatory bowel disease of TCR-β- x TCR-δ-deficient mice. J. Parasitol. 85, 1100–1105 (1999).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Wesemann, D. R. et al. Immature B cells preferentially switch to IgE with increased direct Sμ to Sɛ recombination. J. Exp. Med. 208, 2733–2746 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. 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).

    Article  CAS  PubMed  Google Scholar 

  103. Wang, T. et al. γδ T cells facilitate adaptive immunity against West Nile virus infection in mice. J. Immunol. 177, 1825–1832 (2006).

    Article  CAS  PubMed  Google Scholar 

  104. Nishimura, H. et al. Intraepithelial γδ T cells may bridge a gap between innate immunity and acquired immunity to herpes simplex virus type 2. J. Virol. 78, 4927–4930 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Lafarge, X. et al. Cytomegalovirus infection in transplant recipients resolves when circulating γδ T lymphocytes expand, suggesting a protective antiviral role. J. Infect. Dis. 184, 533–541 (2001).

    Article  CAS  PubMed  Google Scholar 

  106. Pitard, V. et al. Long-term expansion of effector/memory Vδ2 γδ T cells is a specific blood signature of CMV infection. Blood 112, 1317–1324 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Sutton, C. E., Mielke, L. A. & Mills, K. H. IL-17-producing γδ T cells and innate lymphoid cells. Eur. J. Immunol. 42, 2221–2231 (2012).

    Article  CAS  PubMed  Google Scholar 

  108. Tsuji, M. et al. Development of antimalaria immunity in mice lacking IFN-γ receptor. J. Immunol. 154, 5338–5344 (1995).

    CAS  PubMed  Google Scholar 

  109. D'Ombrain, M. C. Hansen, D. S., Simpson, K. M. & Schofield, L. γδ-T cells expressing NK receptors predominate over NK cells and conventional T cells in the innate IFN-γ response to Plasmodium falciparum malaria. Eur. J. Immunol. 37, 1864–1873 (2007).

    Article  CAS  PubMed  Google Scholar 

  110. Girardi, M. & Hayday, A. C. Immunosurveillance by γδ T cells: focus on the murine system. Chem. Immunol. Allergy 86, 136–150 (2005).

    Article  CAS  PubMed  Google Scholar 

  111. Tree, T. I. et al. Naturally arising human CD4 T-cells that recognize islet autoantigens and secrete interleukin-10 regulate proinflammatory T-cell responses via linked suppression. Diabetes 59, 1451–1460 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Peng, S. L., Madaio, M. P., 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 

  113. Cai, Y. et al. Pivotal role of dermal IL-17-producing γδ T cells in skin inflammation. Immunity 35, 596–610 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Pantelyushin, S. et al. Rorγt+ innate lymphocytes and γδ T cells initiate psoriasiform plaque formation in mice. J. Clin. Invest. 122, 2252–2256 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Laggner, U. et al. Identification of a novel proinflammatory human skin-homing Vγ9Vδ2 T cell subset with a potential role in psoriasis. J. Immunol. 187, 2783–2793 (2011).

    Article  CAS  PubMed  Google Scholar 

  116. Petermann, F. et al. γδ T cells enhance autoimmunity by restraining regulatory T cell responses via an interleukin-23-dependent mechanism. Immunity 33, 351–363 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Sutton, C. E. et al. Interleukin-1 and IL-23 induce innate IL-17 production from γδ T cells, amplifying Th17 responses and autoimmunity. Immunity 31, 331–341 (2009).

    Article  CAS  PubMed  Google Scholar 

  118. Wakita, D. et al. Tumor-infiltrating IL-17-producing γδ T cells support the progression of tumor by promoting angiogenesis. Eur. J. Immunol. 40, 1927–1937 (2010).

    Article  CAS  PubMed  Google Scholar 

  119. Vincent, M. S. et al. Lyme arthritis synovial γδ T cells respond to Borrelia burgdorferi lipoproteins and lipidated hexapeptides. J. Immunol. 161, 5762–5771 (1998).

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  121. Johnson, R. M. et al. A murine CD4, CD8 T cell receptor-γδ T lymphocyte clone specific for herpes simplex virus glycoprotein I. J. Immunol. 148, 983–988 (1992).

    CAS  PubMed  Google Scholar 

  122. Hudspeth, K. et al. Engagement of NKp30 on Vδ1 T cells induces the production of CCL3, CCL4, and CCL5 and suppresses HIV-1 replication. Blood 119, 4013–4016 (2012).

    Article  CAS  PubMed  Google Scholar 

  123. Ebert, L. M., Meuter, S. & Moser, B. Homing and function of human skin γδ T cells and NK cells: relevance for tumor surveillance. J. Immunol. 176, 4331–4336 (2006).

    Article  CAS  PubMed  Google Scholar 

  124. Pociask, D. A. et al. γδ T cells attenuate bleomycin-induced fibrosis through the production of CXCL10. Am. J. Pathol. 178, 1167–1176 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Tagawa, T. et al. Vδ1+ γδ T cells producing CC chemokines may bridge a gap between neutrophils and macrophages in innate immunity during Escherichia coli infection in mice. J. Immunol. 173, 5156–5164 (2004).

    Article  CAS  PubMed  Google Scholar 

  126. Boismenu, R., Feng, L., Xia, Y. Y., Chang, J. C. & Havran, W. L. Chemokine expression by intraepithelial γδ T cells. Implications for the recruitment of inflammatory cells to damaged epithelia. J. Immunol. 157, 985–992 (1996).

    CAS  PubMed  Google Scholar 

  127. Matsue, H., Bergstresser, P. R. & Takashima, A. Reciprocal cytokine-mediated cellular interactions in mouse epidermis: promotion of γδ T-cell growth by IL-7 and TNFα and inhibition of keratinocyte growth by γIFN. J. Invest. Dermatol. 101, 543–548 (1993).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank many colleagues, within our laboratory and beyond it, including B. Silva-Santos, J. Kisielow, P. Fisch, L. Lefrancois, R. Tigelaar and W. Born, for thoughtful input and clarification of data, and we thank the Wellcome Trust and Cancer Research UK for funding. We apologize to those whose findings we may have inadvertently overlooked or that were a victim of space constraints.

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Glossary

V(D)J recombination

The somatic rearrangement of variable (V), diversity (D) and joining (J) regions of the genes that encode antigen receptors, leading to repertoire diversity of both B cell and T cell receptors.

Dendritic epidermal γδ T cells

(DETCs). γδ T cell receptor (TCR)-expressing cells selectively localized in the epidermis that have been described 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.

Non-obese diabetic mice

(NOD mice). An inbred strain of mice that spontaneously develop T cell-mediated autoimmune diabetes, which is dependent on their expression of the MHC class II molecule I-Ag7.

B-1 cells

IgMhiIgDlowMAC1+B220lowCD23 cells that are dominant in the peritoneal and pleural cavities. Their precursors develop in the fetal liver and omentum, and in adult mice the size of the B-1 cell population is kept constant owing to the self-renewing capacity of these cells. B-1 cells recognize self components, as well as common bacterial antigens, and they secrete antibodies that tend to have a low affinity and a broad specificity.

Lymphoid stress-surveillance

The capacity of lymphocytes, as opposed to myelomonocytic cells, to sense infection or tissue dysregulation and to respond rapidly, in synchrony with innate responses.

NKG2D

(Natural killer group 2, member D). A lectin-type activating receptor expressed by most NK cells and NKT cells, by many γδ T cells and by antigen-experienced cytolytic CD8+ αβ T cells. NKG2D in humans recognizes MHC class I polypeptide-related sequence A (MICA) and MICB, and at least four related ULBP family proteins, and in mice recognizes multiple members of the structurally related retinoic acid early transcript 1 (RAE1) and H60 families and MULT1. Such ligands are generally expressed at the surface of infected, stressed or transformed cells.

Stress antigens

Molecules, such as MICA and RAE1, that are upregulated by cellular dysregulation and are recognized by lymphocytes as part of a process of immune surveillance.

Signals 1, 2 and 3

Cell signalling pathways that are activated by the engagement of the antigen receptor (signal 1), co-stimulatory receptors such as CD28 (signal 2) and cytokine receptors such as the interleukin-2 receptor (signal 3).

Anergic

A state in which a T cell is almost completely non-responsive to TCR engagement. This may occur when a peripheral T cell is exposed to an antigen in the absence of co-stimulation, and it is interpreted as a means to suppress potentially autoreactive T cell responses in the absence of infection.

Intraepithelial lymphocytes

(IELs). T cells that reside in the basolateral side of an epithelium, above the basement membrane. They express either an αβ TCR or a γδ TCR, and in the murine gut they frequently express the CD8αα homodimer rather than the CD8αβ heterodimer that is expressed by conventional CD8+ T cells in the lymph nodes and by another subset of IELs. It has been proposed that CD8αα+ IELs are self-reactive, TCR agonist-selected cells that have regulatory properties.

Germinal centres

Highly specialized and dynamic microenvironments that give rise to secondary B cell follicles during an immune response. They are the main site of B cell maturation, leading to the generation of memory B cells and plasma cells that produce high-affinity antibodies.

Leaky mutation

A mutation that results in partial rather than complete inactivation of the wild-type function.

Autoimmune regulator

(AIRE). A transcription factor that is expressed by medullary thymic epithelial cells (mTECs) and promotes the promiscuous expression of genes that are otherwise specific to individual peripheral tissues. Peptides derived from these tissue-specific antigens are presented by mTECs to developing αβ T cells, and any T cells with high-affinity TCRs may be clonally deleted as a means of central tolerance.

MRL–lpr mice

A mouse strain that spontaneously develops glomerulonephritis and other symptoms of systemic lupus erythematosus (SLE). The lpr mutation causes a defect in CD95 (also known as FAS), preventing the apoptosis of activated lymphocytes. The MRL strain contributes disease-associated mutations that have yet to be identified.

Imiquimod

An imidazoquinoline-based compound that is sensed by TLR7. It is currently used for the treatment of basal cell carcinoma, but it has also been implicated in iatrogenic induction of psoriasis-like symptoms.

Autoinflammatory diseases

Diseases that are characterized by seemingly unprovoked pathological activation of the innate immune system in the absence of overt autoantibodies or autoreactive T cells.

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Vantourout, P., Hayday, A. Six-of-the-best: unique contributions of γδ T cells to immunology. Nat Rev Immunol 13, 88–100 (2013). https://doi.org/10.1038/nri3384

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