title: The role of HLA-DQ8 beta57 polymorphism in the anti-gluten T-cell response in coeliac disease.
abstract: Major histocompatibility complex (MHC) class II alleles HLA-DQ8 and the mouse homologue I-A(g7) lacking a canonical aspartic acid residue at position beta57 are associated with coeliac disease and type I diabetes. 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 residues on the basis of their spacing to proline residues. 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 activation and that T-cell responses against native gluten peptides are found, particularly in children. Here we show that beta57 polymorphism promotes the recruitment of T-cell receptors bearing a negative signature charge in the complementary determining region 3beta (CDR3beta) 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 CDR3beta. Thus, the lack of a negative charge at position beta57 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.
authors.affiliation: Department of Medicine, Pathology, Pediatrics and Committee of Immunology, University of Chicago, Chicago, Illinois 60637, USA.
authors.forename: Zaruhi
authors.initials: Z
authors.lastname: Hovhannisyan
authors.forename: Angela
authors.initials: A
authors.lastname: Weiss
authors.forename: Alexandra
authors.initials: A
authors.lastname: Martin
authors.forename: Martina
authors.initials: M
authors.lastname: Wiesner
authors.forename: Stig
authors.initials: S
authors.lastname: Tollefsen
authors.forename: Kenji
authors.initials: K
authors.lastname: Yoshida
authors.forename: Cezary
authors.initials: C
authors.lastname: Ciszewski
authors.forename: Shane A
authors.initials: SA
authors.lastname: Curran
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Murray
authors.forename: Chella S
authors.initials: CS
authors.lastname: David
authors.forename: Ludvig M
authors.initials: LM
authors.lastname: Sollid
authors.forename: Frits
authors.initials: F
authors.lastname: Koning
authors.forename: Luc
authors.initials: L
authors.lastname: Teyton
authors.forename: Bana
authors.initials: B
authors.lastname: Jabri
mesh_terms: D000577:Amides / Q000737:chemistry; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002446:Celiac Disease / Q000235:genetics* / Q000276:immunology*; D022801:Complementarity Determining Regions / Q000737:chemistry / Q000276:immunology; D003429:Cross Reactions; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000276:immunology; D005903:Gliadin / Q000737:chemistry / Q000276:immunology; D005983:Glutens / Q000737:chemistry / Q000276:immunology*; D006683:HLA-DQ Antigens / Q000737:chemistry / Q000235:genetics* / Q000276:immunology; D006801:Humans; D006825:Hybridomas / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D011110:Polymorphism, Genetic / Q000235:genetics*; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry / Q000276:immunology; D055672:Static Electricity
chemical_list: D000577:Amides; D022801:Complementarity Determining Regions; D018984:Epitopes, T-Lymphocyte; D006683:HLA-DQ Antigens; C109756:HLA-DQ8 antigen; D011948:Receptors, Antigen, T-Cell; D005983:Glutens; D005903:Gliadin