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Structural basis for the killing of human beta cells by CD8+ T cells in type 1 diabetes

Abstract

The structural characteristics of the engagement of major histocompatibility complex (MHC) class II–restricted self antigens by autoreactive T cell antigen receptors (TCRs) is established, but how autoimmune TCRs interact with complexes of self peptide and MHC class I has been unclear. Here we examined how CD8+ T cells kill human islet beta cells in type 1 diabetes via recognition of a human leukocyte antigen HLA-A*0201–restricted glucose-sensitive preproinsulin peptide by the autoreactive TCR 1E6. Rigid 'lock-and-key' binding underpinned the 1E6–HLA-A*0201–peptide interaction, whereby 1E6 docked similarly to most MHC class I–restricted TCRs. However, this interaction was extraordinarily weak because of limited contacts with MHC class I. TCR binding was highly peptide centric, dominated by two residues of the complementarity-determining region 3 (CDR3) loops that acted as an 'aromatic-cap' over the complex of peptide and MHC class I (pMHCI). Thus, highly focused peptide-centric interactions associated with suboptimal TCR-pMHCI binding affinities might lead to thymic escape and potential CD8+ T cell–mediated autoreactivity.

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Figure 1: The CD8+ T cell clone 1E6 kills unmanipulated human islets from various donors without any requirement for cytokine treatment or the addition of exogenous cognate self peptide.
Figure 2: Mutational scan of the 1E6 CD8+ T cell clone.
Figure 3: Binding interface of 1E6–A2-ALW.
Figure 4: Interactions of the 1E6 TCR with HLA-A*0201.
Figure 5: Interactions of the 1E6 TCR with ALW.

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Acknowledgements

We thank the staff at Diamond Light Source for facilities and support; M. Zhao for help preparing human islets; and J. Todd for INS genotyping. Supported by the Biotechnology and Biological Sciences Research Council (BB/H001085/1), the Wellcome Trust (WT086716 to A.K.S.; WT079848 to L.W.; and WT095767 to D.K.C.), the Juvenile Diabetes Research Foundation (7-2005-877 and 1-2007-1803 to M.P.; and 17-2009-806 to A.K.S., M.P., D.A.P. and A.S.), the European Union Seventh Framework Programme (241447 NAIMIT), the National Institute for Health Research Comprehensive Biomedical Research Center at Guy's & St. Thomas' National Health Service Foundation Trust and King's College London, Research Councils UK (P.J.R.), the National Health and Medical Research Council (J.R.), the Welsh Office of Research and Development (J.J.M.) and the Medical Research Council (D.A.P.).

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D.K.C., P.J.R., M.P. and A.K.S., leadership and project conception; D.K.C. and A.M.B., crystallization and surface plasmon resonance studies; D.K.C., A.M.B., F.M., J.J.M., P.J.R. and A.F., data and crystal collection; D.K.C., S.G. and P.J.R., crystallographic analysis; A.S., J.W.D. and R.R.K., cell experiments; G.C.H., preparation of human islets; G.D., T cell culture; E.G., N.L. and P.E.M., cloning of the 1E6 TCR; D.K.C., A.K.S., M.P., P.J.R., J.J.M., J.R. and S.G., manuscript authorship; L.W. and B.K.J., intellectual input; and A.K.S., M.P., D.A.P. and J.R., study funding.

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Correspondence to Andrew K Sewell.

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Bulek, A., Cole, D., Skowera, A. et al. Structural basis for the killing of human beta cells by CD8+ T cells in type 1 diabetes. Nat Immunol 13, 283–289 (2012). https://doi.org/10.1038/ni.2206

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