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

Nat Commun. 2021 Aug 25;12(1):5110. doi: 10.1038/s41467-021-25404-x.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • CD4-Positive T-Lymphocytes / chemistry
  • CD4-Positive T-Lymphocytes / metabolism
  • Diabetes Mellitus, Type 1 / genetics
  • Diabetes Mellitus, Type 1 / metabolism*
  • HLA-DQ Antigens / chemistry
  • HLA-DQ Antigens / genetics
  • HLA-DQ Antigens / metabolism*
  • Humans
  • Insulin / chemistry
  • Insulin / genetics
  • Insulin / metabolism*
  • Peptides / chemistry
  • Peptides / metabolism*
  • Protein Binding
  • Receptors, Antigen, T-Cell / chemistry
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Antigen, T-Cell / metabolism*


  • HLA-DQ Antigens
  • HLA-DQ8 antigen
  • Insulin
  • Peptides
  • Receptors, Antigen, T-Cell