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

Nature communications 2021 Aug 25

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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. © 2021. The Author(s).

Citation

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 La Gruta, Anthony W Purcell, Stuart I Mannering, Jamie Rossjohn, Hugh H Reid. T cell receptor recognition of hybrid insulin peptides bound to HLA-DQ8. Nature communications. 2021 Aug 25;12(1):5110