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Nat Struct Mol Biol. 2020 Jan;27(1):49-61. doi: 10.1038/s41594-019-0353-4. Epub 2019 Dec 23.

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

Author information

1
Infection and Immunity Program and The Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute Monash University, Clayton, Victoria, Australia.
2
Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria, Australia.
3
Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands.
4
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
5
Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.
6
Department of Microbiology & Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia.
7
ImmusanT, Cambridge, MA, USA.
8
Department of Gastroenterology, The Royal Melbourne Hospital, Parkville, Victoria, Australia.
9
Infection and Immunity Program and The Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute Monash University, Clayton, Victoria, Australia. hugh.reid@monash.edu.
10
Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria, Australia. hugh.reid@monash.edu.
11
Infection and Immunity Program and The Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute Monash University, Clayton, Victoria, Australia. jamie.rossjohn@monash.edu.
12
Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria, Australia. jamie.rossjohn@monash.edu.
13
Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK. jamie.rossjohn@monash.edu.

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.

PMID:
31873306
DOI:
10.1038/s41594-019-0353-4

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