T cell receptor cross-reactivity between gliadin and bacterial peptides in celiac disease

Petersen, Jan, Ciacchi, Laura, Tran, Mai T., Loh, Khai Lee, Kooy-Winkelaar, Yvonne, Croft, Nathan P., Hardy, Melinda Y., Chen, Zhenjun, McCluskey, James, Anderson, Robert P., Purcell, Anthony W., Tye-Din, Jason A., Koning, Frits, Reid, Hugh H. and Rossjohn, Jamie ORCID: https://orcid.org/0000-0002-2020-7522 2020. T cell receptor cross-reactivity between gliadin and bacterial peptides in celiac disease. Nature Structural and Molecular Biology 27 (1) , pp. 49-61. 10.1038/s41594-019-0353-4

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Abstract

The human leukocyte antigen (HLA) locus is strongly associated with T cell-mediated autoimmune disorders. HLA-DQ2.5-mediated celiac disease (CeD) is triggered by the ingestion of gluten, although the relative roles of genetic and environmental risk factors in CeD is unclear. Here we identify microbially derived mimics of gliadin epitopes and a parental bacterial protein that is naturally processed by antigen-presenting cells and activated gliadin reactive HLA-DQ2.5-restricted T cells derived from CeD patients. Crystal structures of T cell receptors in complex with HLA-DQ2.5 bound to two distinct bacterial peptides demonstrate that molecular mimicry underpins cross-reactivity toward the gliadin epitopes. Accordingly, gliadin reactive T cells involved in CeD pathogenesis cross-react with ubiquitous bacterial peptides, thereby suggesting microbial exposure as a potential environmental factor in CeD.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Publisher:	Nature Publishing Group
ISSN:	1545-9993
Date of First Compliant Deposit:	31 January 2020
Date of Acceptance:	18 November 2019
Last Modified:	06 Nov 2023 22:22
URI:	https://orca.cardiff.ac.uk/id/eprint/129211

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