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Cytomegalovirus and tumor stress surveillance by binding of a human γδ T cell antigen receptor to endothelial protein C receptor

Nature Immunology volume 13, pages 872–879 (2012)Cite this article

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Abstract

T cells bearing γδ T cell antigen receptors (TCRs) function in lymphoid stress surveillance. However, the contribution of γδ TCRs to such responses is unclear. Here we found that the TCR of a human Vγ4Vδ5 clone directly bound endothelial protein C receptor (EPCR), which allowed γδ T cells to recognize both endothelial cells targeted by cytomegalovirus and epithelial tumors. EPCR is a major histocompatibility complex–like molecule that binds lipids analogously to the antigen-presenting molecule CD1d. However, the Vγ4Vδ5 TCR bound EPCR independently of lipids, in an antibody-like way. Moreover, the recognition of target cells by γδ T cells required a multimolecular stress signature composed of EPCR and costimulatory ligand(s). Our results demonstrate how a γδ TCR mediates recognition of broadly stressed human cells by engaging a stress-regulated self antigen.

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Figure 1: LES TCR–mediated recognition of target cells is blocked by mAb 2E9.
Figure 2: Identification of EPCR as the 2E9 ligand.
Figure 3: EPCR directly binds LES γδ TCR.
Figure 4: EPCR specificity of Vδ2− γδ T cell populations.
Figure 5: Effect of infection with CMV and expression of EPCR on recognition by LES cells.
Figure 6: The LES TCR binds EPCR independently of lipid presentation.
Figure 7: Activation of the LES clone by CMV-infected cells depends on constitutive and CMV-induced costimulatory molecules.

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Acknowledgements

We thank M.-L. Michel, M. Swamy and F. Mohammed for contributions to this project; D. Price for discussions; and V. Venturi for analysis of TCR nontemplated nucleotide additions. Supported by Fondation pour la Recherche Médicale (DEQ20051205738 and DEQ20110421287), Agence Nationale de la Recherche (ANR-05-JCJC-0129-01), Ligue Nationale contre le Cancer, Association pour la Recherche sur le Cancer (A09-1-5022), Institut National contre le Cancer (INCa TUMOSTRESS) Cancer Research UK (C17422-A7986 and C17422-A11740 to B.E.W., supporting C.R.W. and M.S.), the Wellcome Trust (T.S. and A.C.H.) and Boehringer Ingelheim Fonds (T.S. and A.C.H.).

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Author notes

  1. Carrie R Willcox, Vincent Pitard, Benjamin E Willcox and Julie Déchanet-Merville: These authors contributed equally to this work.

Authors and Affiliations

  1. Birmingham Cancer Research UK Cancer Centre, School of Cancer Sciences, University of Birmingham, Birmingham, UK

    Carrie R Willcox, Mahboob Salim & Benjamin E Willcox

  2. Composantes innées de la réponse immunitaire et différenciation, Unité Mixte de Recherche 5164, Université de Bordeaux, Bordeaux, France

    Vincent Pitard, Sonia Netzer, Lionel Couzi, Jean-François Moreau & Julie Déchanet-Merville

  3. Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5164, Bordeaux, France

    Vincent Pitard, Sonia Netzer, Lionel Couzi, Jean-François Moreau & Julie Déchanet-Merville

  4. Renal Transplantation Department, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France

    Lionel Couzi

  5. Peter Gorer Department of Immunobiology, King's College London Medical School, Guy's Hospital, London, UK

    Tobias Silberzahn & Adrian C Hayday

  6. London Research Institute, Cancer Research UK, London, UK

    Tobias Silberzahn & Adrian C Hayday

  7. Immunology Department, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France

    Jean-François Moreau

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Contributions

C.R.W. and V.P. did most of the experiments, analyzed data and designed experiments; S.N., L.C. and M.S. did experiments and analyzed data; T.S. did gene profiling and analysis; J.-F.M. helped supervise research; and A.C.H., B.E.W., J.D.-M. analyzed and interpreted data, designed and supervised research and wrote the manuscript.

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Correspondence to Benjamin E Willcox or Julie Déchanet-Merville.

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The authors declare no competing financial interests.

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Supplementary Figures 1–5 (PDF 391 kb)

Supplementary Table 1

Illumina expression profiling of 2E9L+ vs 2E9L(−) cell lines (XLS 48 kb)

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Willcox, C., Pitard, V., Netzer, S. 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). https://doi.org/10.1038/ni.2394

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