Major histocompatibility complex (MHC) class II alleles HLA-DQ8 and the mouse homologue I-Ag7 lacking a canonical aspartic acid residue at position β57 are associated with coeliac disease1,2 and type I diabetes3,4. However, the role of this single polymorphism in disease initiation and progression remains poorly understood. The lack of Asp 57 creates a positively charged P9 pocket, which confers a preference for negatively charged peptides. Gluten lacks such peptides, but tissue transglutaminase (TG2) introduces negatively charged residues at defined positions into gluten T-cell epitopes by deamidating specific glutamine residues5,6 on the basis of their spacing to proline residues7. The commonly accepted model, proposing that HLA-DQ8 simply favours binding of negatively charged peptides, does not take into account the fact that TG2 requires inflammation for activation8 and that T-cell responses against native gluten peptides are found9,10, particularly in children11. Here we show that β57 polymorphism promotes the recruitment of T-cell receptors bearing a negative signature charge in the complementary determining region 3β (CDR3β) during the response against native gluten peptides presented by HLA-DQ8 in coeliac disease. These T cells showed a crossreactive and heteroclitic (stronger) response to deamidated gluten peptides. Furthermore, gluten peptide deamidation extended the T-cell-receptor repertoire by relieving the requirement for a charged residue in CDR3β. Thus, the lack of a negative charge at position β57 in MHC class II was met by negatively charged residues in the T-cell receptor or in the peptide, the combination of which might explain the role of HLA-DQ8 in amplifying the T-cell response against dietary gluten.
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We thank S. Sadegh-Nasseri for advice and discussion, and A. Bendelac and M. Mush for critical reading of the manuscript. This work was supported by the Digestive Disease Research Core Center of the University of Chicago (DK42086), NIH DK67180, DK55037, the Celiac Disease Consortium (F.K.), EU MC-RTN 512385 (M.W.), the Research Council of Norway (L.S.) and the University of Oslo (S.T.).
Author Contributions Z.H. executed most of the studies, participated in conceptual development and in the preparation of the manuscript; A.W., A.M., C.C., S.A.C., K.Y. provided technical assistance and input into data analysis. M.W., S.T., L.M.S. and F.K. generated and characterized human T-cell clones. C.S.D. and J.A.M. provided humanized HLA-DQ8 transgenic mice. F.K. and L.M.S. reviewed the manuscript. L.T. provided input into conceptual development and experimental design. B.J. developed the concept, supervised all investigations and wrote the manuscript.
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Hovhannisyan, Z., Weiss, A., Martin, A. et al. The role of HLA-DQ8 β57 polymorphism in the anti-gluten T-cell response in coeliac disease. Nature 456, 534–538 (2008) doi:10.1038/nature07524
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