8VD2

Human TCR ET650-4 in complex with DQ8-InsC8-15-IAPP1

Summary for 8VD2

• Entry DOI: 10.2210/pdb8vd2/pdb
• Related: 8VCX 8VCY 8VD0 8VDD 8VDU
• Descriptor: MHC class II HLA-DQ-alpha chain, MHC class II HLA-DQ-beta-1, Hybrid insulin peptide (HIP; InsC8-15-IAPP23-29 ), ... (7 entities in total)
• Functional Keywords: immune t cell receptor-pmhc ii complex, immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 95526.47

Authors

Tran, T.M.,Lim, J.J.,Loh, T.Y.,Mannering, I.S.,Rossjohn, J.,Reid, H.H. (deposition date: 2023-12-14, release date: 2024-08-07, Last modification date: 2024-10-09)

Primary citation

Tran, M.T.,Lim, J.J.,Loh, T.J.,Mannering, S.I.,Rossjohn, J.,Reid, H.H.
A structural basis of T cell cross-reactivity to native and spliced self-antigens presented by HLA-DQ8.
J.Biol.Chem., 300:107612-107612, 2024

PubMed 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 (PI GQVELGGGPGAGSLQ) but also cross-react with a hybrid insulin peptide (HIP; PI-IAPP 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 PI epitope and multiple HIPs fused at the same N-terminus (PI) to the degradation products of two highly expressed pancreatic islet proteins, neuropeptide Y (NPY) and amyloid polypeptide (IAPP and IAPP). 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 PI and HIP epitopes. Crystal structures of two TRAV26-1-TRBV5-1 T cell receptors (TCRs) in complex with PI and HIPs bound to HLA-DQ8 revealed that the two TCRs had distinct mechanisms responsible for their differential recognition of the PI and HIP epitopes. Alanine scanning mutagenesis of the PI 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.

PubMed: 39074636
DOI: 10.1016/j.jbc.2024.107612

Experimental method

X-RAY DIFFRACTION (2.9 Å)