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Antagonists and non-toxic variants of the dominant wheat gliadin T cell epitope in coeliac disease

Background: Coeliac disease (CD) is due to an inappropriate T cell mediated response to specific gluten peptides. Measured by interferon γ (IFN-γ) ELISPOT, about half of the gliadin specific T cells induced with in vivo wheat gluten exposure in HLA-DQ2+ CD are specific for an α/β-gliadin peptide (p57–73 QE65; QLQPFPQPELPYPQPQS) that includes two overlapping T cell epitopes (PFPQPELPY and PQPELPYPQ). Aim: To define minimally substituted variants of p57–73 QE65 universally devoid of IFN-γ stimulatory capacity but capable of antagonising IFN-γ secretion from polyclonal T cells specific for p57–73 QE65. Methods: Peripheral blood mononuclear cells collected from 75 HLA-DQ2+ CD patients after in vivo gluten challenge were used in overnight ELISPOT assays to screen 218 single or double substituted variants of p57–73 QE65 for cytokine stimulatory and antagonist activity. Results: The region p60–71 (PFPQPELPYPQP) and especially p64–67 (PELP) was sensitive to substitution. Twelve substitutions in p64–67 stimulated no IFN-γ ELISPOT response. Among 131 partial agonists identified, 45 produced statistically significant inhibition of IFN-γ ELISPOT responses when cocultured in fivefold excess with p57–73 QE65 (n = 10). Four substituted variants of p57–73 QE65 were inactive by IFN-γ ELISPOT but consistently antagonised IFN-γ ELISPOT responses to p57–73 QE65, and also retained interleukin 10 stimulatory capacity similar to p57–73 QE65. Conclusions: Altered peptide ligands of p57–73 QE65, identified using polyclonal T cells from multiple HLA-DQ2+ CD donors, have properties in vitro that suggest that a single substitution to certain α/β-gliadins could abolish their capacity to stimulate IFN-γ from CD4 T cells and also have anti-inflammatory or protective effects in HLA-DQ2+ CD.