Comprehensive, Quantitative Mapping of T Cell Epitopes in Gluten in Celiac Disease — Sci TM

Sci Transl Med 21 July 2010:
Vol. 2, Issue 41, p. 41ra51
DOI: 10.1126/scitranslmed.3001012

Research Article
Comprehensive, Quantitative Mapping of T Cell Epitopes in Gluten in Celiac Disease
Jason A. Tye-Din1,2,3,*, Jessica A. Stewart1,*, James A. Dromey1,*, Tim Beissbarth1,*†, David A. van Heel4, Arthur Tatham5, Kate Henderson6, Stuart I. Mannering1,‡, Carmen Gianfrani7, Derek P. Jewell8, Adrian V. S. Hill9, James McCluskey10, Jamie Rossjohn6 and Robert P. Anderson1,3,§
+ Author Affiliations

1Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia.
2Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010, Australia.
3Department of Gastroenterology, Royal Melbourne Hospital, Grattan Street, Parkville, Victoria 3050, Australia.
4Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.
5Cardiff School of Health Sciences, University of Wales Institute, Cardiff CF5 2YB, UK.
6Protein Crystallography Unit, Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria 3800, Australia.
7Institute of Food Science, National Research Council, Via Roma 52, 83100 Avellino, Italy.
8Nuffield Department of Medicine, University of Oxford, Oxford OX3 9DU, UK.
9Jenner Institute, University of Oxford, Oxford OX3 9DU, UK.
10Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria 3010, Australia.

§To whom correspondence should be addressed. E-mail: banderson@wehi.edu.au

Abstract
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.

Footnotes
↵* 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).

Copyright © 2010, American Association for the Advancement of Science
Comprehensive, Quantitative Mapping of T Cell Epitopes in Gluten in Celiac Disease — Sci TM