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

Jan Petersen; Laura Ciacchi; Mai T Tran; Khai Lee Loh; Yvonne Kooy-Winkelaar; Nathan P Croft; Melinda Y Hardy; Zhenjun Chen; James McCluskey; Robert P Anderson; Anthony W Purcell; Jason A Tye-Din; Frits Koning; Hugh H Reid; Jamie Rossjohn

Journal article

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

Jan Petersen, Laura Ciacchi, Mai T Tran, Khai Lee Loh, Yvonne Kooy-Winkelaar, Nathan P Croft, Melinda Y Hardy, Zhenjun Chen, James McCluskey, Robert P Anderson, Anthony W Purcell, Jason A Tye-Din, Frits Koning, Hugh H Reid, Jamie Rossjohn

Nature Structural & Molecular Biology | NATURE PUBLISHING GROUP | Published : 2019

DOI: 10.1038/s41594-019-0353-4

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 gliad..

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University of Melbourne Researchers

Melinda Hardy Author Medical Biology (W.E.H.I.)

Jason Tye-Din Author Medical Biology (W.E.H.I.)

James McCluskey Author

Zhenjun Chen Author Microbiology and Immunology

Grants

Awarded by National Health and Medical Research Council of Australia (NHMRC)

Awarded by Australian Research Council (ARC)

Awarded by PPP allowance

Funding Acknowledgements

We thank the staff at the Australian Synchrotron for assistance with data collection and the staff at the Monash Macromolecular crystallization facility. We thank the CeD volunteers who participated in this study. This work was supported by grants from the National Health and Medical Research Council of Australia (NHMRC, program grant no. APP1113293) and the Australian Research Council (ARC, grant no. CE140100011). F.K. is supported by the collaboration project TIMID (no. LSHM18057-SGF) financed by the PPP allowance made available by Top Sector Life Sciences and Health to Samenwerkende Gezondheidsfondsen (SGF) to stimulate public-private partnerships and co-financing by health foundations that are part of the SGF. A.W.P. is supported by an NHMRC Principal Research Fellowship. J.R. is supported by an ARC Laureate Fellowship.