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

Mai T. Tran, Pouya Faridi, Jia Jia Lim, Yi Tian Ting, Goodluck Onwukwe, Pushpak Bhattacharjee, Claerwen M. Jones, Eleonora Tresoldi, Fergus J. Cameron, Nicole L. Gruta, Anthony W. Purcell, Stuart I. Mannering, Jamie Rossjohn () and Hugh H. Reid ()
Additional contact information
Mai T. Tran: Biomedicine Discovery Institute, Monash University
Pouya Faridi: Biomedicine Discovery Institute, Monash University
Jia Jia Lim: Biomedicine Discovery Institute, Monash University
Yi Tian Ting: Biomedicine Discovery Institute, Monash University
Goodluck Onwukwe: Biomedicine Discovery Institute, Monash University
Pushpak Bhattacharjee: Immunology and Diabetes Unit, St Vincent’s Institute of Medical Research
Claerwen M. Jones: Biomedicine Discovery Institute, Monash University
Eleonora Tresoldi: Immunology and Diabetes Unit, St Vincent’s Institute of Medical Research
Fergus J. Cameron: Murdoch Children’s Research Institute
Nicole L. Gruta: Biomedicine Discovery Institute, Monash University
Anthony W. Purcell: Biomedicine Discovery Institute, Monash University
Stuart I. Mannering: Immunology and Diabetes Unit, St Vincent’s Institute of Medical Research
Jamie Rossjohn: Biomedicine Discovery Institute, Monash University
Hugh H. Reid: Biomedicine Discovery Institute, Monash University

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: 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 structure of three TRBV5+ TCR-HLA-DQ8-HIP complexes shows that the TRBV5-encoded TCR β-chain forms a common landing pad on the HLA-DQ8 molecule. The N- and C-termini of the HIP is recognised predominantly by the TCR α-chain and TCR β-chain, respectively, in all three TCR ternary complexes. Accordingly, TRBV5 + TCR recognition of HIP peptides might occur via a ‘polarised’ mechanism, whereby each chain within the αβTCR heterodimer recognises distinct origins of the spliced peptide presented by HLA-DQ8.

Date: 2021
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DOI: 10.1038/s41467-021-25404-x

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