T cell receptor recognition of hybrid insulin peptides bound to HLA-DQ8

MT Tran; P Faridi; JJ Lim; YT Ting; G Onwukwe; P Bhattacharjee; CM Jones; E Tresoldi; FJ Cameron; NL La Gruta; AW Purcell; SI Mannering; J Rossjohn; HH Reid

Journal article

T cell receptor recognition of hybrid insulin peptides bound to HLA-DQ8

MT Tran, P Faridi, JJ Lim, YT Ting, G Onwukwe, P Bhattacharjee, CM Jones, E Tresoldi, FJ Cameron, NL La Gruta, AW Purcell, SI Mannering, J Rossjohn, HH Reid

Nature Communications | Published : 2021

DOI: 10.1038/s41467-021-25404-x

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Abstract

HLA-DQ8, a genetic risk factor in type I diabetes (T1D), presents hybrid insulin peptides (HIPs) to autoreactive CD4+ T cells. The abundance of spliced peptides binding to HLA-DQ8 and how they are subsequently recognised by the autoreactive T cell repertoire is unknown. Here we report, the HIP (GQVELGGGNAVEVLK), derived from splicing of insulin and islet amyloid polypeptides, generates a preferred peptide-binding motif for HLA-DQ8. HLA-DQ8-HIP tetramer+ T cells from the peripheral blood of a T1D patient are characterised by repeated TRBV5 usage, which matches the TCR bias of CD4+ T cells reactive to the HIP peptide isolated from the pancreatic islets of a patient with T1D. The crystal struct..

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University of Melbourne Researchers

Fergus Cameron Author

Jamie Rossjohn Author

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Funding Acknowledgements

We thank the staff at the Australian Synchrotron for assistance with data collection, the staff at the Monash Macromolecular Crystallisation Facility, and Dr. Martin Davey for assistance with statistical analysis. This work was supported by grants from the National Health and Medical Research Council of Australia (NHMRC, Project Grant No. APP1123586, S.I.M. H.H.R and Programme Grant No. APP1113293, J.R.) and the Australian Research Council (ARC, Grant No. CE140100011, J.R.). P.F. is supported by the Victorian Department of Health and Human Services acting through the Victorian Cancer Agency. A.W.P. is supported by an NHMRC Principal Research Fellowship. J.R. is supported by an ARC Laureate Fellowship.