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Celiac disease is a genetic condition that results in a debilitating immune reaction in the gut to antigens in grain. The antigenic peptides recognized by the T cells that cause this disease are incompletely defined. Our understanding of the epitopes of pathogenic CD4+ T cells is based primarily on responses shown by intestinal T-cells in vitro to hydrolysates or polypeptides of gluten, the causative antigen. A protease-resistant 33-amino acid peptide from wheat α-gliadin is the immunodominant antigen, but little is known about the spectrum of T cell epitopes in rye and barley or the hierarchy of immunodominance and consistency of recognition of T-cell epitopes in vivo. We induced polyclonal gluten-specific T cells in the peripheral blood of celiac patients by feeding them cereal and performed a comprehensive, unbiased analysis of responses to all celiac toxic prolamins, a class of plant storage protein. The peptides that stimulated T cells were the same among patients who ate the same cereal, but were different after wheat, barley and rye ingestion. Unexpectedly, a sequence from ω-gliadin (wheat) and C-hordein (barley) but not α-gliadin was immunodominant regardless of the grain consumed. Furthermore, T cells specific for just three peptides accounted for the majority of gluten-specific T cells, and their recognition of gluten peptides was highly redundant. Our findings show that pathogenic T cells in celiac disease show limited diversity, and therefore suggest that peptide-based therapeutics for this disease and potentially other strongly HLA-restricted immune diseases should be possible.
↵* These authors contributed equally to this work.
↵† Present address: Department of Medical Statistics, University Medicine Goettingen, 37099 Goettingen, Germany.
↵‡ Present address: St. Vincent’s Institute of Medical Research, 41 Victoria Parade, Fitzroy, Victoria 3065, Australia.
Citation: J. A. Tye-Din, J. A. Stewart, J. A. Dromey, T. Beissbarth, D. A. van Heel, A. Tatham, K. Henderson, S. I. Mannering, C. Gianfrani, D. P. Jewell, A. V. S. Hill, J. McCluskey, J. Rossjohn, R. P. Anderson, Comprehensive, quantitative mapping of T cell epitopes in gluten in celiac disease.Sci. Transl. Med. 2, 41ra51 (2010).
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