A TCRα framework–centered codon shapes a biased T cell repertoire through direct MHC and CDR3β interactions

• DOI: 10.1172/jci.insight.95193
• Publication Date: 2017-09-06T21:27:40Z
• Authors: Kristin Støen Gun...; Lene Støkken Høydahl; Louise Fremgaard ...; Shiva Dahal-Koirala; Ralf Stefan Neumann; Elin Bergseng; Terje Frigstad; Rahel Frick; M. Fleur du Pré; Bjørn Dalhus; Knut E.A. Lundin; Shuo-Wang Qiao; Ludvig M. Sollid; Inger Sandlie; Geir Åge Løset
• Keywords: CD4-Positive T-Lymphocytes; 0301 basic medicine; 570; Glutens; Receptors, Antigen, T-Cell, alpha-beta; 610; Epitopes, T-Lymphocyte; Lymphocyte Activation; Complementarity Determining Regions; Clone Cells; 3. Good health; Major Histocompatibility Complex; Celiac Disease; 03 medical and health sciences; HLA-DQ Antigens; Humans; Cloning, Molecular; Codon

Selection of biased T cell receptor (TCR) repertoires across individuals is seen in both infectious diseases and autoimmunity, but the underlying molecular basis leading to these shared remains unclear. Celiac disease (CD) occurs primarily HLA-DQ2.5+ characterized by a CD4+ response against gluten epitopes dominated DQ2.5-glia-α1a DQ2.5-glia-α2. The DQ2.5-glia-α2 recruits highly TCR repertoire composed TRAV26-1 paired with TRBV7-2 harboring semipublic CDR3β loop. We aimed unravel for this signature. By variable gene segment exchange, directed mutagenesis, cellular activation studies, we found that TRBV7-3 can substitute TRBV7-2, as contain canonical Furthermore, identified pivotal germline-encoded MHC recognition motif centered on framework residue Y40 engaging DQB1*02 CDR3β. This allowed prediction expanded DQ2.5-glia-α2–reactive repertoires, which were confirmed single-cell sorting sequencing from CD patient samples. Our data refine our understanding how HLA-dependent are selected periphery due residues.