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

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16 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)49-61
Number of pages13
JournalNature Structural & Molecular Biology
Volume27
DOIs
Publication statusPublished - Jan 2020

Keywords

  • immunology
  • x-ray crystallography

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