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

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.

Neoantigens: promising targets for cancer therapy

“…199 There is evidence that neoantigens involving the linkage of existing individual peptides can activate CD4 + T cells in type 1 diabetes (T1D), indicating that proteomic variants processes may generate MHC-II-associated neoantigens. 200 Several studies have reported that the spliced peptides produced by the proteasome are able to activate CD8 + T cells. 198,201,202 Splicetope-specific CD8 + T cells from TILs isolated from human AML patients inhibited the growth of their corresponding tumor cells in severe combined immunodeficient (SCID) mice model.…”

Glutamine deamidation does not increase the immunogenicity of C-peptide in people with type 1 diabetes

“…It can also respond to C-peptide which comprises half of the HIP. It responds moderately to full-length C-peptide (PI 33-63 ), but weakly to an 18mer fragment of C-peptide (PI 38-54 ) [ 36 ]. This allowed us to validate our system with a set of peptides known to vary in their capacity to stimulate this clone.…”

Structural plasticity in I-Ag7 links autoreactivity to hybrid insulin peptides in type I diabetes

“…Instead, the scarce polar contacts seen in the three reported human TCR : HIP/DQ8 pairs are mediated by backbone oxygen and nitrogen atoms. Remarkably, however, the peptides bound to HLA-DQ8 molecules in the B-lymphoblastoid 9033 cell line were found to be highly enriched for presence of acidic residues at positions P5, P7 and P8 ( 37 ). This observation suggests that recognition of human HIPs carrying acidic residues at these positions by DQ8-restricted TCRs might be dictated by further molecular mechanisms that share common features with the 4.1-TCR : HIP39/I-A g7 signature.…”

“…Recent structures of human TCRs bound to a HIP/HLA-DQ8 pMHCII complex ( 37 ) enable cross-species comparison for MHCII-presentation of HIPs. Despite the natural divergence in both the TCR repertoire and MHCII sequences, HIP presentation and recognition in the human and murine contexts follow a classical TCR:pMHCII binding pattern.…”