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Sci Adv. 2019 Aug 21;5(8):eaaw9336. doi: 10.1126/sciadv.aaw9336. eCollection 2019 Aug.

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

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Benaroya Research Institute at Virginia Mason, 1201 9th Ave., Seattle, WA 98101, USA.
Laboratory of Biophysics, Biochemistry, Bioprocessing and Bioproducts, Faculty of Agricultural Technology, Technological Educational Institute of Epirus, GR47100 Arta, Greece.
Department of Food Technology, Ionian University, GR28100 Argostoli, Cephallonia, Greece.
Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.
Department of Immunology, University of Washington, Seattle, WA 98195, USA.
Department of Medicine, University of Washington, Seattle, WA 98195, USA.


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 α chain of HLA-DQ8 transdimer in complex with the disease-relevant GAD65250-266 peptide and in silico analysis reveal the DQ α52 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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