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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.

Author information

1
Benaroya Research Institute at Virginia Mason, 1201 9th Ave., Seattle, WA 98101, USA.
2
Laboratory of Biophysics, Biochemistry, Bioprocessing and Bioproducts, Faculty of Agricultural Technology, Technological Educational Institute of Epirus, GR47100 Arta, Greece.
3
Department of Food Technology, Ionian University, GR28100 Argostoli, Cephallonia, Greece.
4
Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.
5
Department of Immunology, University of Washington, Seattle, WA 98195, USA.
6
Department of Medicine, University of Washington, Seattle, WA 98195, USA.

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 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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