Comprehensive, quantitative mapping of T cell epitopes in gluten in celiac disease.
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 alpha-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 omega-gliadin (wheat) and C-hordein (barley) but not alpha-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.
Tye-Din
Jason A
JA
Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia.
Stewart
Jessica A
JA
Dromey
James A
JA
Beissbarth
Tim
T
van Heel
David A
DA
Tatham
Arthur
A
Henderson
Kate
K
Mannering
Stuart I
SI
Gianfrani
Carmen
C
Jewell
Derek P
DP
Hill
Adrian V S
AV
McCluskey
James
J
Rossjohn
Jamie
J
Anderson
Robert P
RP
D000328:Adult; D000368:Aged; D002446:Celiac Disease / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005260:Female; D005903:Gliadin / Q000276:immunology; D005983:Glutens / Q000276:immunology*; D001467:Hordeum / Q000276:immunology; D006801:Humans; D008297:Male; D008875:Middle Aged; D010455:Peptides / Q000276:immunology; D012434:Secale / Q000276:immunology; D014908:Triticum / Q000276:immunology; D055815:Young Adult
D018984:Epitopes, T-Lymphocyte; D010455:Peptides; D005983:Glutens; D005903:Gliadin