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

Abstract

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.

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Acknowledgements

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). https://doi.org/10.1038/s41590-018-0253-5

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