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The γδTCR combines innate immunity with adaptive immunity by utilizing spatially distinct regions for agonist selection and antigen responsiveness


T lymphocytes expressing γδ T cell antigen receptors (TCRs) comprise evolutionarily conserved cells with paradoxical features. On the one hand, clonally expanded γδ T cells with unique specificities typify adaptive immunity. Conversely, large compartments of γδTCR+ intraepithelial lymphocytes (γδ IELs) exhibit limited TCR diversity and effect rapid, innate-like tissue surveillance. The development of several γδ IEL compartments depends on epithelial expression of genes encoding butyrophilin-like (Btnl (mouse) or BTNL (human)) members of the B7 superfamily of T cell co-stimulators. Here we found that responsiveness to Btnl or BTNL proteins was mediated by germline-encoded motifs within the cognate TCR variable γ-chains (Vγ chains) of mouse and human γδ IELs. This was in contrast to diverse antigen recognition by clonally restricted complementarity-determining regions CDR1–CDR3 of the same γδTCRs. Hence, the γδTCR intrinsically combines innate immunity and adaptive immunity by using spatially distinct regions to discriminate non-clonal agonist-selecting elements from clone-specific ligands. The broader implications for antigen-receptor biology are considered.

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Fig. 1: Primary Vγ7+ IELs exhibit a semi-invariant TCR usage.
Fig. 2: Expression of mouse Vγ7+ TCR confers responsiveness to Btnl1 and Btnl6.
Fig. 3: Expression of human Vγ4+ TCR confers responsiveness to BTNL3 and BTNL8.
Fig. 4: Human Vγ4HV4 is a critical determinant of the response to BTNL3 plus BTNL8.
Fig. 5: Cross-species conservation of the critical role of HV4γ in the response to Btnl or BTNL proteins.
Fig. 6: A proposed model for engagement of BTNL3 by Vγ4+ TCRs.
Fig. 7: Human Vγ4+ TCRs and mouse Vγ7+ TCRs exhibit dual reactivity.

Data availability

This work did not include any data with mandated deposition in public databases. Associated raw data are provided in the main and/or supplementary figures. Relations to summary data charts are indicated and a full list of figures with associated raw data is provided in the Reporting Summary linked to this article.


  1. 1.

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

    CAS  Article  Google Scholar 

  2. 2.

    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  Google Scholar 

  3. 3.

    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  Google Scholar 

  4. 4.

    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).

    CAS  Article  Google Scholar 

  5. 5.

    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).

    CAS  Article  Google Scholar 

  6. 6.

    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).

    CAS  Article  Google Scholar 

  7. 7.

    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).

    CAS  Article  Google Scholar 

  8. 8.

    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).

    CAS  Article  Google Scholar 

  9. 9.

    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).

    CAS  Article  Google Scholar 

  10. 10.

    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).

    CAS  Article  Google Scholar 

  11. 11.

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

    CAS  Article  Google Scholar 

  12. 12.

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

    CAS  Article  Google Scholar 

  13. 13.

    Havran, W. L., Carbone, A. & Allison, J. P. Murine T cells with invariant γδ antigen receptors: origin, repertoire, and specificity. Semin. Immunol. 3, 89–97 (1991).

    CAS  PubMed  Google Scholar 

  14. 14.

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

    CAS  Article  Google Scholar 

  15. 15.

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

    CAS  Article  Google Scholar 

  16. 16.

    Medzhitov, R. & Janeway, C. A. Jr. Innate immunity: the virtues of a nonclonal system of recognition. Cell 91, 295–298 (1997).

    CAS  Article  Google Scholar 

  17. 17.

    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).

    CAS  Article  Google Scholar 

  18. 18.

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

    CAS  Article  Google Scholar 

  19. 19.

    Leishman, A. J. et al. Precursors of functional MHC class I- or class II-restricted CD8αα+ T cells are positively selected in the thymus by agonist self-peptides. Immunity 16, 355–364 (2002).

    CAS  Article  Google Scholar 

  20. 20.

    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).

    CAS  Article  Google Scholar 

  21. 21.

    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).

    CAS  Article  Google Scholar 

  22. 22.

    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  Google Scholar 

  23. 23.

    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).

    CAS  Article  Google Scholar 

  24. 24.

    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).

    CAS  Article  Google Scholar 

  25. 25.

    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).

    CAS  Article  Google Scholar 

  26. 26.

    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).

    CAS  Article  Google Scholar 

  27. 27.

    Goodman, T. & Lefrancois, L. Intraepithelial lymphocytes. Anatomical site, not T cell receptor form, dictates phenotype and function. J. Exp. Med. 170, 1569–1581 (1989).

    CAS  Article  Google Scholar 

  28. 28.

    San José, E., Borroto, A., Niedergang, F., Alcover, A. & Alarcón, B. Triggering the TCR complex causes the downregulation of nonengaged receptors by a signal transduction-dependent mechanism. Immunity 12, 161–170 (2000).

    Article  Google Scholar 

  29. 29.

    Heemskerk, M. H. et al. Redirection of antileukemic reactivity of peripheral T lymphocytes using gene transfer of minor histocompatibility antigen HA-2-specific T-cell receptor complexes expressing a conserved alpha joining region. Blood 102, 3530–3540 (2003).

    CAS  Article  Google Scholar 

  30. 30.

    Moran, A. E. et al. T cell receptor signal strength in Treg and iNKT cell development demonstrated by a novel fluorescent reporter mouse. J. Exp. Med. 208, 1279–1289 (2011).

    CAS  Article  Google Scholar 

  31. 31.

    Chancellor, A. et al. CD1b-restricted GEM T cell responses are modulated by Mycobacterium tuberculosis mycolic acid meromycolate chains. Proc. Natl. Acad. Sci. USA 114, E10956–E10964 (2017).

    CAS  Article  Google Scholar 

  32. 32.

    Kabelitz, D. et al. New monoclonal antibody (23D12) recognizing three different Vγ elements of the human γδ T cell receptor. 23D12+ cells comprise a major subpopulation of γδ T cells in postnatal thymus. J. Immunol. 152, 3128–3136 (1994).

    CAS  PubMed  Google Scholar 

  33. 33.

    Hayes, S. M., Shores, E. W. & Love, P. E. An architectural perspective on signaling by the pre-, αβ and γδ T cell receptors. Immunol. Rev. 191, 28–37 (2003).

    CAS  Article  Google Scholar 

  34. 34.

    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).

    CAS  Article  Google Scholar 

  35. 35.

    Bates, P. A., Kelley, L. A., MacCallum, R. M. & Sternberg, M. J. Enhancement of protein modeling by human intervention in applying the automatic programs 3D-JIGSAW and 3D-PSSM. Proteins 5, 39–46 (2001).

    Article  Google Scholar 

  36. 36.

    Torchala, M., Moal, I. H., Chaleil, R. A., Fernandez-Recio, J. & Bates, P. A. SwarmDock: a server for flexible protein-protein docking. Bioinformatics 29, 807–809 (2013).

    CAS  Article  Google Scholar 

  37. 37.

    Holness, C. L. & Simmons, D. L. Structural motifs for recognition and adhesion in members of the immunoglobulin superfamily. J. Cell Sci. 107, 2065–2070 (1994).

    CAS  PubMed  Google Scholar 

  38. 38.

    Green, N. et al. Mutational analysis of MAdCAM-1/α4β7 interactions reveals significant binding determinants in both the first and second immunuglobulin domains. Cell Adhes. Commun. 7, 167–181 (1999).

    CAS  Article  Google Scholar 

  39. 39.

    Jones, E. Y. et al. Crystal structure of an integrin-binding fragment of vascular cell adhesion molecule-1 at 1.8 Å resolution. Nature 373, 539–544 (1995).

    CAS  Article  Google Scholar 

  40. 40.

    Moebius, U., Pallai, P., Harrison, S. C. & Reinherz, E. L. Delineation of an extended surface contact area on human CD4 involved in class II major histocompatibility complex binding. Proc. Natl. Acad. Sci. USA 90, 8259–8263 (1993).

    CAS  Article  Google Scholar 

  41. 41.

    Somoza, C., Driscoll, P. C., Cyster, J. G. & Williams, A. F. Mutational analysis of the CD2/CD58 interaction: the binding site for CD58 lies on one face of the first domain of human CD2. J. Exp. Med. 178, 549–558 (1993).

    CAS  Article  Google Scholar 

  42. 42.

    Myers, D. R., Zikherman, J. & Roose, J. P. Tonic signals: why do lymphocytes bother? Trends Immunol. 38, 844–857 (2017).

    CAS  Article  Google Scholar 

  43. 43.

    Hayday, A. & Vantourout, P. A long-playing CD about the γδ TCR repertoire. Immunity 39, 994–996 (2013).

    CAS  Article  Google Scholar 

  44. 44.

    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).

    CAS  Article  Google Scholar 

  45. 45.

    Fahl, S. P. et al. Role of a selecting ligand in shaping the murine γδ-TCR repertoire. Proc. Natl. Acad. Sci. USA 115, 1889–1894 (2018).

    CAS  Article  Google Scholar 

  46. 46.

    Wencker, M. et al. Innate-like T cells straddle innate and adaptive immunity by altering antigen-receptor responsiveness. Nat. Immunol. 15, 80–87 (2014).

    CAS  Article  Google Scholar 

  47. 47.

    Sumaria, N., Grandjean, C. L., Silva-Santos, B. & Pennington, D. J. Strong TCRγδ signaling prohibits thymic development of iL-17A-secreting γδ T cells. Cell Reports 19, 2469–2476 (2017).

    CAS  Article  Google Scholar 

  48. 48.

    Cernadas, M. et al. Lysosomal localization of murine CD1d mediated by AP-3 is necessary for NK T cell development. J. Immunol. 171, 4149–4155 (2003).

    CAS  Article  Google Scholar 

  49. 49.

    Chiu, Y. H. et al. Multiple defects in antigen presentation and T cell development by mice expressing cytoplasmic tail-truncated CD1d. Nat. Immunol. 3, 55–60 (2002).

    CAS  Article  Google Scholar 

  50. 50.

    Mallevaey, T. et al. T cell receptor CDR2β and CDR3β loops collaborate functionally to shape the iNKT cell repertoire. Immunity 31, 60–71 (2009).

    CAS  Article  Google Scholar 

  51. 51.

    Bueno, C. et al. Bacterial superantigens bypass Lck-dependent T cell receptor signaling by activating a Gα11-dependent, PLC-β-mediated pathway. Immunity 25, 67–78 (2006).

    CAS  Article  Google Scholar 

  52. 52.

    Fields, B. A. et al. Crystal structure of a T-cell receptor β-chain complexed with a superantigen. Nature 384, 188–192 (1996).

    CAS  Article  Google Scholar 

  53. 53.

    Kreiss, M. et al. Contrasting contributions of complementarity-determining region 2 and hypervariable region 4 of rat BV8S2+ (Vβ8.2) TCR to the recognition of myelin basic protein and different types of bacterial superantigens. Int. Immunol. 16, 655–663 (2004).

    CAS  Article  Google Scholar 

  54. 54.

    Hayakawa, K. et al. Positive selection of natural autoreactive B cells. Science 285, 113–116 (1999).

    CAS  Article  Google Scholar 

  55. 55.

    Meyer, S. et al. AIRE-deficient patients harbor unique high-affinity disease-ameliorating autoantibodies. Cell 166, 582–595 (2016).

    CAS  Article  Google Scholar 

  56. 56.

    Mansour, S. et al. Cholesteryl esters stabilize human CD1c conformations for recognition by self-reactive T cells. Proc. Natl. Acad. Sci. USA 113, E1266–E1275 (2016).

    CAS  Article  Google Scholar 

  57. 57.

    Zennou, V., Perez-Caballero, D., Göttlinger, H. & Bieniasz, P. D. APOBEC3G incorporation into human immunodeficiency virus type 1 particles. J. Virol. 78, 12058–12061 (2004).

    CAS  Article  Google Scholar 

  58. 58.

    Fouchier, R. A., Meyer, B. E., Simon, J. H., Fischer, U. & Malim, M. H. HIV-1 infection of non-dividing cells: evidence that the amino-terminal basic region of the viral matrix protein is important for Gag processing but not for post-entry nuclear import. EMBO J. 16, 4531–4539 (1997).

    CAS  Article  Google Scholar 

  59. 59.

    O’Shea, E. K., Lumb, K. J. & Kim, P. S. Peptide ‘Velcro’: design of a heterodimeric coiled coil. Curr. Biol. 3, 658–667 (1993).

    Article  Google Scholar 

  60. 60.

    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).

    CAS  Article  Google Scholar 

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We are grateful to D. Kaiserlian (INSERM U1111, Lyon) for MODE-K cells; P. Pereira (Institut Pasteur) for the hybridoma (F2.67) producing antibody to Vγ7+ TCR; C. Willcox (University of Birmingham), B. Willcox (University of Birmingham) and P. Barral (The Francis Crick Institute) for cell lines; R.P. Di Marco Barros, A. Jandke, A. Lorenc, D. Ushakov and A. Laing for contributions and discussions; E. Theodoridis, the flow cytometry, genomic equipment park, bio-informatics, experimental histopathology, mass spectrometry and proteomics platform, cell services, and biological service units of the Francis Crick Institute, the Peter Gorer Department of Immunobiology and the Guy’s Hospital Biomedical Research Centre (BRC) for outstanding technical support; and the NVIDIA corporation for the donation of a Titan Xp GPU used to run our protein–protein docking algorithm. The work was supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (CRUK) (FC001003), the UK Medical Research Council (FC001003), and the Wellcome Trust (FC001003); the CRUK King’s Cancer Centre; studentships from the King’s Bioscience Institute and the Guy’s and St. Thomas’ Charity Prize PhD program in Biomedical and Translational Science (D.M.), the National Institute for Health Research (NIHR) Biomedical Research Centre at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London (to I.Z.), and the Wellcome Trust (108745/Z/15/Z) (R.J.D.); funds from St. Thomas’ Wegener’s Trust and MRC (MR/P021964/1) (S.J.), the Cluster of Excellence ExC 306 ‘Inflammation-at-Interfaces’ (D.W. and D.K.), Cancer Research UK (23562) (S.M.), and the Wellcome Trust (106292/Z/14/Z and 100156/Z/12/Z) (A.C.H.). This manuscript is dedicated to the memory of Dr. Bruno Kyewski, who greatly clarified our insights into T cell tolerance and selection.

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D.M., I.Z., R.A.G.C., R.J.D., N.A.R., S.J. and P.V. designed and undertook experiments; A.C., O.N., O.P., D.W., D.K. and S.M. designed, prepared and provided critical reagents, D.M., I.Z., R.A.G.C., R.J.D., N.A.R., P.M.I., S.J., S.M., P.A.B., P.V. and A.C.H. processed and interpreted data; D.M., I.Z., R.J.D. and N.A.R revised the manuscript; and P.V. and A.C.H. designed the study and wrote the manuscript.

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Correspondence to Pierre Vantourout or Adrian C. Hayday.

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O.N. and O.P. are employees of GammdaDelta Therapeutics; and O.N., O.P. and A.C.H. are equity holders in GammaDelta Therapeutics.

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Melandri, D., Zlatareva, I., Chaleil, R.A.G. 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).

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