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γδ TCR ligands: the quest to solve a 500-million-year-old mystery

Nature Immunology volume 20, pages 121–128 (2019)Cite this article

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A Publisher Correction to this article was published on 28 February 2019

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Abstract

γδ T cells have been retained as a lineage over the majority of vertebrate evolution, are able to respond to immune challenges in unique ways, and are of increasing therapeutic interest. However, one central mystery has endured: the identity of the ligands recognized by the γδ T cell antigen receptor. Here we discuss the inherent challenges in answering this question, the new opportunities provided by recent studies, and the criteria by which the field might judge success.

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Fig. 1: Selected candidate ligands for the γδ TCR.
Fig. 2: Various approaches for the identification of candidate ligands for the γδ TCR.
Fig. 3: Ligand engagement in the context of adaptive γδ T cell function.
Fig. 4: BTN and BTNL molecules in the selection and activation of γδ T cells.

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  • 28 February 2019

    In the version of this article initially published, the affiliations were incorrect. The correct affiliations are as follows: “1Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK. 2Institute of Immunology and Immunotherapy, Cancer Immunology and Immunotherapy Centre, Cancer Research UK Birmingham Centre, University of Birmingham, Birmingham, UK.” The reference citation at the end of the first sentence of the second paragraph of the subsection ‘A perspective on current methods of ligand identification’ was incorrect; the correct citation is “...ligands20–40.” There is an error (en dash) in the fourth paragraph of that section; the correct text is “...specific for CD1 and phycoerythrin...”. There is an error (“proposed”) in the fourth paragraph of the subsection ‘An emerging adaptive perspective on antigenic γδ TCR ligands’; the correct text is “...are suggested to recognize...”. There is an error (“via”) in the fourth paragraph of the subsection ‘B7-like molecules as candidate γδ TCR ligands’; the correct text is “...in a non-clonotypic fashion are striking...”. Finally, reference citations throughout the legend to Fig. 1 are incorrect; the correct citations are as follows: MHC class I free heavy chain22; HLA-B580234; I-Ek (ref. 30); MSH2 (MutShomolog 2) and HSP60 (heat-shock protein 60)24; ULBP4 (UL16-binding protein 4)27; MICA41; the herpes simplex virus glycoprotein HSVgI33; ATPase–apolipoprotein-AI39; and insulin B:9-23 peptide antigen40. The errors have been corrected in the HTML and PDF versions of the article.

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).

    Article  CAS  PubMed  Google Scholar 

  2. Hirano, M. et al. Evolutionary implications of a third lymphocyte lineage in lampreys. Nature 501, 435–438 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Vantourout, P. & Hayday, A. Six-of-the-best: unique contributions of γδ T cells to immunology. Nat. Rev. Immunol. 13, 88–100 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. De Libero, G. et al. Selection by two powerful antigens may account for the presence of the major population of human peripheral γδ T cells. J. Exp. Med. 173, 1311–1322 (1991).

    Article  PubMed  Google Scholar 

  5. Khairallah, C., Déchanet-Merville, J. & Capone, M. γδ T cell-mediated immunity to cytomegalovirus infection. Front. Immunol. 8, 105 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  6. Khairallah, C. et al. γδ T cells confer protection against murine cytomegalovirus (MCMV). PLoS Pathog. 11, e1004702 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  7. Sell, S. et al. Control of murine cytomegalovirus infection by γδ T cells. PLoS Pathog. 11, e1004481 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  9. Halary, F. et al. Shared reactivity of Vδ2neg 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 

  10. Gentles, A. J. et al. The prognostic landscape of genes and infiltrating immune cells across human cancers. Nat. Med. 21, 938–945 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  12. García, V. E. et al. IL-15 enhances the response of human γδ T cells to nonpeptide microbial antigens. J. Immunol. 160, 4322–4329 (1998).

    PubMed  Google Scholar 

  13. García, V. E. et al. IL-18 promotes type 1 cytokine production from NK cells and T cells in human intracellular infection. J. Immunol. 162, 6114–6121 (1999).

    PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  16. Kalyan, S. & Kabelitz, D. Defining the nature of human γδ T cells: a biographical sketch of the highly empathetic. Cell. Mol. Immunol. 10, 21–29 (2013).

    Article  CAS  PubMed  Google Scholar 

  17. Grusby, M. J. et al. Mice lacking major histocompatibility complex class I and class II molecules. Proc. Natl Acad. Sci. USA 90, 3913–3917 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Davis, M. M. & Bjorkman, P. J. T-cell antigen receptor genes and T-cell recognition. Nature 334, 395–402 (1988).

    Article  CAS  PubMed  Google Scholar 

  19. Gomes, A. Q., Martins, D. S. & Silva-Santos, B. Targeting γδ T lymphocytes for cancer immunotherapy: from novel mechanistic insight to clinical application. Cancer Res. 70, 10024–10027 (2010).

    Article  CAS  PubMed  Google Scholar 

  20. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Barbee, S. D. et al. Skint-1 is a highly specific, unique selecting component for epidermal T cells. Proc. Natl Acad. Sci. USA 108, 3330–3335 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Bonneville, M. et al. Chicago 2014-30 years of γδ T cells. Cell. Immunol. 296, 3–9 (2015).

    Article  CAS  PubMed  Google Scholar 

  23. 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 

  24. Chen, H. et al. Identification of human T cell receptor γδ-recognized epitopes/proteins via CDR3delta peptide-based immunobiochemical strategy. J. Biol. Chem. 283, 12528–12537 (2008).

    Article  CAS  PubMed  Google Scholar 

  25. 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).

    Article  CAS  PubMed  Google Scholar 

  26. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Kong, Y. et al. The NKG2D ligand ULBP4 binds to TCRγ9/δ2 and induces cytotoxicity to tumor cells through both TCRγδ and NKG2D. Blood 114, 310–317 (2009).

    Article  CAS  PubMed  Google Scholar 

  28. Luoma, A. M. et al. Crystal structure of Vδ1 T cell receptor in complex with CD1d-sulfatide shows MHC-like recognition of a self-lipid by human γδ T cells. Immunity 39, 1032–1042 (2013).

    Article  CAS  PubMed  Google Scholar 

  29. Marlin, R. et al. Sensing of cell stress by human γδ TCR-dependent recognition of annexin A2. Proc. Natl Acad. Sci. USA 114, 3163–3168 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. 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 

  31. Melandri, D. et al. The γδTCR combines innate immunity with adaptive immunity by utilizing spatially distinct regions for agonist selection and antigen responsiveness. Nat. Immunol. 19, 1352–1365 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Roy, S. et al. Molecular analysis of lipid-reactive Vδ1 γδ T cells identified by CD1c tetramers. J. Immunol. 196, 1933–1942 (2016).

    Article  CAS  PubMed  Google Scholar 

  33. Sciammas, R. & Bluestone, J. A. HSV-1 glycoprotein I-reactive TCR γδ cells directly recognize the peptide backbone in a conformationally dependent manner. J. Immunol. 161, 5187–5192 (1998).

    CAS  PubMed  Google Scholar 

  34. Silva-Santos, B., Schamel, W. W., Fisch, P. & Eberl, M. γδ T-cell conference 2012: close encounters for the fifth time. Eur. J. Immunol. 42, 3101–3105 (2012).

    Article  CAS  PubMed  Google Scholar 

  35. Uldrich, A. P. et al. CD1d-lipid antigen recognition by the γδ TCR. Nat. Immunol. 14, 1137–1145 (2013).

    Article  CAS  PubMed  Google Scholar 

  36. 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. Nat. Immunol. 13, 872–879 (2012).

    Article  CAS  PubMed  Google Scholar 

  37. 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 

  38. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. 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 

  40. Aydintug, M. K. et al. γδ T cells recognize the insulin B:9-23 peptide antigen when it is dimerized through thiol oxidation. Mol. Immunol. 60, 116–128 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  41. 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).

    Article  CAS  PubMed  Google Scholar 

  42. Exley, M. A. & Koziel, M. J. To be or not to be NKT: natural killer T cells in the liver. Hepatology 40, 1033–1040 (2004).

    Article  PubMed  Google Scholar 

  43. Rhodes, D. A., Reith, W. & Trowsdale, J. Regulation of immunity by butyrophilins. Annu. Rev. Immunol. 34, 151–172 (2016).

    Article  CAS  PubMed  Google Scholar 

  44. Vantourout, P. et al. Heteromeric interactions regulate butyrophilin (BTN) and BTN-like molecules governing γδ T cell biology. Proc. Natl Acad. Sci. USA 115, 1039–1044 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Sandstrom, A. et al. The intracellular B30.2 domain of butyrophilin 3A1 binds phosphoantigens to mediate activation of human Vγ9Vδ2 T cells. Immunity 40, 490–500 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Vavassori, S. et al. Butyrophilin 3A1 binds phosphorylated antigens and stimulates human γδ T cells. Nat. Immunol. 14, 908–916 (2013).

    Article  CAS  PubMed  Google Scholar 

  47. Jönsson, P. et al. Remarkably low affinity of CD4/peptide-major histocompatibility complex class II protein interactions. Proc. Natl Acad. Sci. USA 113, 5682–5687 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  48. 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 

  49. Di Marco Barros, R. et al. Epithelia use butyrophilin-like molecules to shape organ-specific γδ T cell compartments. Cell 167, 203–218 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  50. 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 

  51. Willcox, C. R., Davey, M. S. & Willcox, B. E. Development and selection of the human Vγ9Vδ2+ T-cell repertoire. Front. Immunol. 9, 1501 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  52. Davey, M. S., Willcox, C. R., Baker, A. T., Hunter, S. & Willcox, B. E. Recasting human Vδ1 lymphocytes in an adaptive role. Trends Immunol. 39, 446–459 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Davey, M. S. et al. The human Vδ2+ T-cell compartment comprises distinct innate-like Vγ9+ and adaptive Vγ9- subsets. Nat. Commun. 9, 1760 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  54. Davey, M. S. et al. Clonal selection in the human Vδ1 T cell repertoire indicates γδ TCR-dependent adaptive immune surveillance. Nat. Commun. 8, 14760 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  55. Davey, M. S., Willcox, C. R., Hunter, S., Oo, Y. H. & Willcox, B. E. V. Vδ2+ T cells—two subsets for the price of one. Front. Immunol. 9, 2106 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  56. Hunter, S. et al. Human liver infiltrating γδ T cells are composed of clonally expanded circulating and tissue-resident populations. J. Hepatol. 69, 654–665 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Ravens, S. et al. Human γδ T cells are quickly reconstituted after stem-cell transplantation and show adaptive clonal expansion in response to viral infection. Nat. Immunol. 18, 393–401 (2017).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  59. Mamedov, M. R. et al. A macrophage colony-stimulating-factor-producing γδ T cell subset prevents malarial parasitemic recurrence. Immunity 48, 350–363 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Burnet, F. M. A modification of Jerne’s theory of antibody production using the concept of clonal selection. Aust. J. Sci. 20, 67–69 (1957).

    Google Scholar 

  61. Lafarge, X. et al. Expression of MHC class I receptors confers functional intraclonal heterogeneity to a reactive expansion of γδ T cells. Eur. J. Immunol. 35, 1896–1905 (2005).

    Article  CAS  PubMed  Google Scholar 

  62. Ribot, J. C., Ribeiro, S. T., Correia, D. V., Sousa, A. E. & Silva-Santos, B. Human γδ thymocytes are functionally immature and differentiate into cytotoxic type 1 effector T cells upon IL-2/IL-15 signaling. J. Immunol. 192, 2237–2243 (2014).

    Article  CAS  PubMed  Google Scholar 

  63. Hohlfeld, R., Engel, A. G., Ii, K. & Harper, M. C. Polymyositis mediated by T lymphocytes that express the γδ receptor. N. Engl. J. Med. 324, 877–881 (1991).

    Article  CAS  PubMed  Google Scholar 

  64. Pluschke, G., Rüegg, D., Hohlfeld, R. & Engel, A. G. Autoaggressive myocytotoxic T lymphocytes expressing an unusual γδ T cell receptor. J. Exp. Med. 176, 1785–1789 (1992).

    Article  CAS  PubMed  Google Scholar 

  65. Ugur, M., Kaminski, A. & Pabst, O. Lymph node γδ and αβ CD8+ T cells share migratory properties. Sci. Rep. 8, 8986 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  66. Boyden, L. M. et al. Skint1, the prototype of a newly identified immunoglobulin superfamily gene cluster, positively selects epidermal γδ T cells. Nat. Genet. 40, 656–662 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Chodaczek, G., Papanna, V., Zal, M. A. & Zal, T. Body-barrier surveillance by epidermal γδ TCRs. Nat. Immunol. 13, 272–282 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Salim, M. et al. Characterization of a putative receptor binding surface on Skint-1, a critical determinant of dendritic epidermal T cell selection. J. Biol. Chem. 291, 9310–9321 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Wang, H. & Morita, C. T. Sensor function for butyrophilin 3A1 in prenyl pyrophosphate stimulation of human Vγ2Vδ2 T cells. J. Immunol. 195, 4583–4594 (2015).

    Article  CAS  PubMed  Google Scholar 

  70. Gu, S., Borowska, M. T., Boughter, C. T. & Adams, E. J. Butyrophilin3A proteins and Vγ9Vδ2 T cell activation. Semin. Cell Dev. Biol. 84, 65–74 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Riaño, F. et al. Vγ9Vδ2 TCR-activation by phosphorylated antigens requires butyrophilin 3 A1 (BTN3A1) and additional genes on human chromosome 6. Eur. J. Immunol. 44, 2571–2576 (2014).

    Article  PubMed  Google Scholar 

  72. 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 

  73. Wang, H., Fang, Z. & Morita, C. T. Vγ2Vδ2 T cell receptor recognition of prenyl pyrophosphates is dependent on all CDRs. J. Immunol. 184, 6209–6222 (2010).

    Article  CAS  PubMed  Google Scholar 

  74. Lebrero-Fernández, C. et al. Altered expression of Butyrophilin (BTN) and BTN-like (BTNL) genes in intestinal inflammation and colon cancer. Immun. Inflamm. Dis. 4, 191–200 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

Funded by a Wellcome Trust Investigator Award to B.E.W., supporting C.R.W. (099266/Z/12/Z). We would like to thank Professor Adrian Hayday, Dr Martin Davey, and Dr Pierre Vantourout for fruitful discussions.

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  1. Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK

    Benjamin E. Willcox

  2. Institute of Immunology and Immunotherapy, Cancer Immunology and Immunotherapy Centre, Cancer Research UK Birmingham Centre, University of Birmingham, Birmingham, UK

    Carrie R. Willcox

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Willcox, B.E., Willcox, C.R. γδ TCR ligands: the quest to solve a 500-million-year-old mystery. Nat Immunol 20, 121–128 (2019). https://doi.org/10.1038/s41590-018-0304-y

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