title: Posttranslational modification of gluten shapes TCR usage in celiac disease.
abstract: Posttranslational modification of Ag is implicated in several autoimmune diseases. In celiac disease, a cereal gluten-induced enteropathy with several autoimmune features, T cell recognition of the gluten Ag is heavily dependent on the posttranslational conversion of Gln to Glu residues. Evidence suggests that the enhanced recognition of deamidated gluten peptides results from improved peptide binding to the MHC and TCR interaction with the peptide-MHC complex. In this study, we report that there is a biased usage of TCR Vβ6.7 chain among TCRs reactive to the immunodominant DQ2-α-II gliadin epitope. We isolated Vβ6.7 and DQ2-αII tetramer-positive CD4(+) T cells from peripheral blood of gluten-challenged celiac patients and sequenced the TCRs of a large number of single T cells. TCR sequence analysis revealed in vivo clonal expansion, convergent recombination, semipublic response, and the notable conservation of a non-germline-encoded Arg residue in the CDR3β loop. Functional testing of a prototype DQ2-α-II-reactive TCR by analysis of TCR transfectants and soluble single-chain TCRs indicate that the deamidated residue in the DQ2-α-II peptide poses constraints on the TCR structure in which the conserved Arg residue is a critical element. The findings have implications for understanding T cell responses to posttranslationally modified Ags.
authors.affiliation: Department of Immunology, Centre for Immune Regulation, University of Oslo, 0027 Oslo, Norway. s.w.qiao@medisin.uio.no
authors.forename: Shuo-Wang
authors.initials: SW
authors.lastname: Qiao
authors.forename: Melinda
authors.initials: M
authors.lastname: Ráki
authors.forename: Kristin S
authors.initials: KS
authors.lastname: Gunnarsen
authors.forename: Geir-Åge
authors.initials: GÅ
authors.lastname: Løset
authors.forename: Knut E A
authors.initials: KE
authors.lastname: Lundin
authors.forename: Inger
authors.initials: I
authors.lastname: Sandlie
authors.forename: Ludvig M
authors.initials: LM
authors.lastname: Sollid
mesh_terms: D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002446:Celiac Disease / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D005903:Gliadin / Q000276:immunology; D005983:Glutens / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D016056:Immunodominant Epitopes / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D011499:Protein Processing, Post-Translational / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry / Q000235:genetics* / Q000276:immunology; D020349:Surface Plasmon Resonance
chemical_list: D018984:Epitopes, T-Lymphocyte; D016056:Immunodominant Epitopes; D011948:Receptors, Antigen, T-Cell; D005983:Glutens; D005903:Gliadin