Discriminative T cell recognition of cross-reactive islet-antigens is associated with HLA-DQ8 transdimer–mediated autoimmune diabetes

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Abstract

Human leukocyte antigen (HLA)–DQ8 transdimer (HLA-DQA1*0501/DQB1*0302) confers exceptionally high risk in autoimmune diabetes. However, little is known about HLA-DQ8 transdimer–restricted CD4 T cell recognition, an event crucial for triggering HLA-DQ8 transdimer–specific anti-islet immunity. Here, we report a high degree of epitope overlap and T cell promiscuity between susceptible HLA-DQ8 and HLA-DQ8 transdimer. Despite preservation of putative residues for T cell receptor (TCR) contact, stronger disease-associated responses to cross-reactive, immunodominant islet epitopes are elicited by HLA-DQ8 transdimer. Mutagenesis at the chain of HLA-DQ8 transdimer in complex with the disease-relevant GAD65250–266 peptide and in silico analysis reveal the DQ 52 residue located within the N-terminal edge of the peptide-binding cleft for the enhanced T cell reactivity, altering avidity and biophysical affinity between TCR and HLA-peptide complexes. Accordingly, a structurally promiscuous but nondegenerate TCR-HLA-peptide interface is pivotal for HLA-DQ8 transdimer–mediated autoimmune diabetes.

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Chow, I. T., Gates, T. J., Papadopoulos, G. K., Moustakas, A. K., Kolawole, E. M., Notturno, R. J., … Kwok, W. W. (2019). Discriminative T cell recognition of cross-reactive islet-antigens is associated with HLA-DQ8 transdimer–mediated autoimmune diabetes. Science Advances, 5(8). https://doi.org/10.1126/sciadv.aaw9336

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