A structural basis of T cell cross-reactivity to native and spliced self-antigens presented by HLA-DQ8

J Biol Chem. 2024 Sep;300(9):107612. doi: 10.1016/j.jbc.2024.107612. Epub 2024 Jul 27.

Abstract

Type 1 diabetes (T1D) is a T cell-mediated autoimmune disease that has a strong HLA association, where a number of self-epitopes have been implicated in disease pathogenesis. Human pancreatic islet-infiltrating CD4+ T cell clones not only respond to proinsulin C-peptide (PI40-54; GQVELGGGPGAGSLQ) but also cross-react with a hybrid insulin peptide (HIP; PI40-47-IAPP74-80; GQVELGGG-NAVEVLK) presented by HLA-DQ8. How T cell receptors recognize self-peptide and cross-react to HIPs is unclear. We investigated the cross-reactivity of the CD4+ T cell clones reactive to native PI40-54 epitope and multiple HIPs fused at the same N-terminus (PI40-54) to the degradation products of two highly expressed pancreatic islet proteins, neuropeptide Y (NPY68-74) and amyloid polypeptide (IAPP23-29 and IAPP74-80). We observed that five out of the seven selected SKW3 T cell lines expressing TCRs isolated from CD4+ T cells of people with T1D responded to multiple HIPs. Despite shared TRAV26-1-TRBV5-1 gene usage in some T cells, these clones cross-reacted to varying degrees with the PI40-54 and HIP epitopes. Crystal structures of two TRAV26-1+-TRBV5-1+ T cell receptors (TCRs) in complex with PI40-54 and HIPs bound to HLA-DQ8 revealed that the two TCRs had distinct mechanisms responsible for their differential recognition of the PI40-54 and HIP epitopes. Alanine scanning mutagenesis of the PI40-54 and HIPs determined that the P2, P7, and P8 residues in these epitopes were key determinants of TCR specificity. Accordingly, we provide a molecular basis for cross-reactivity towards native insulin and HIP epitopes presented by HLA-DQ8.

Keywords: T cell receptor cross-reactivity; TCR-pMHC complexes; Type 1 diabetes; autoimmunity; hybrid insulin peptide (HIP); major histocompatibility complex (MHC).

MeSH terms

  • Antigen Presentation
  • Autoantigens* / chemistry
  • Autoantigens* / immunology
  • CD4-Positive T-Lymphocytes* / immunology
  • CD4-Positive T-Lymphocytes* / metabolism
  • Cross Reactions*
  • Crystallography, X-Ray
  • Diabetes Mellitus, Type 1* / immunology
  • Epitopes, T-Lymphocyte / immunology
  • HLA-DQ Antigens* / chemistry
  • HLA-DQ Antigens* / genetics
  • HLA-DQ Antigens* / immunology
  • Humans
  • Islet Amyloid Polypeptide / chemistry
  • Islet Amyloid Polypeptide / genetics
  • Islet Amyloid Polypeptide / immunology
  • Islet Amyloid Polypeptide / metabolism
  • Receptors, Antigen, T-Cell / chemistry
  • Receptors, Antigen, T-Cell / immunology
  • Receptors, Antigen, T-Cell / metabolism

Substances

  • HLA-DQ Antigens
  • HLA-DQ8 antigen
  • Autoantigens
  • Epitopes, T-Lymphocyte
  • Receptors, Antigen, T-Cell
  • Islet Amyloid Polypeptide