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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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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  1. These authors contributed equally: Daisy Melandri, Iva Zlatareva.


  1. Peter Gorer Department of Immunobiology, School of Immunology & Microbial Sciences, King’s College London, London, UK

    • Daisy Melandri
    • , Iva Zlatareva
    • , Robin J. Dart
    • , Natalie A. Roberts
    • , Susan John
    • , Pierre Vantourout
    •  & Adrian C. Hayday
  2. Immunosurveillance Laboratory, The Francis Crick Institute, London, UK

    • Daisy Melandri
    • , Iva Zlatareva
    • , Robin J. Dart
    • , Natalie A. Roberts
    • , Pierre Vantourout
    •  & Adrian C. Hayday
  3. Biomolecular Modelling Laboratory, The Francis Crick Institute, London, UK

    • Raphaël A. G. Chaleil
    •  & Paul A. Bates
  4. Academic Unit of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK

    • Andrew Chancellor
    •  & Salah Mansour
  5. GammaDelta Therapeutics, London BioScience Innovation Center, London, UK

    • Oliver Nussbaumer
    •  & Oxana Polyakova
  6. Institute of Immunology, University Hospital Schleswig-Holstein, Christian-Albrechts University, Kiel, Germany

    • Daniela Wesch
    •  & Dieter Kabelitz
  7. Department of Gastroenterology, Guy’s and St Thomas’ Foundation Trust, London, UK

    • Robin J. Dart
    •  & Peter M. Irving


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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.

Competing interests

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.

Corresponding authors

Correspondence to Pierre Vantourout or Adrian C. Hayday.

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