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.
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The structure models and structure factors for the complexes HLA-DQ2.5–P.fluor-α1a, LS2.8/3.15 TCR–HLA-DQ2.5–P.fluor-α1a, and JR5.1 TCR–HLA-DQ2.5–P.aeru-α2a have been deposited at the wwPDB under accession codes PDB 6U3M, 6U3N, and 6U3O, respectively. The source data for Supplementary Figs 1 and 2 are available online.
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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.
R.P.A. and J.A.T.-D. are inventors of patents owned or licensed by ImmusanT Inc. relating to the diagnostic application of gluten challenge, and use of gluten-derived T cell epitopes for use in therapeutics.
Peer review information Inês Chen was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.
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Petersen, J., Ciacchi, L., Tran, M.T. et al. T cell receptor cross-reactivity between gliadin and bacterial peptides in celiac disease. Nat Struct Mol Biol 27, 49–61 (2020). https://doi.org/10.1038/s41594-019-0353-4
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