title: Islet-associated T-cell receptor-β CDR sequence repertoire in prediabetic NOD mice reveals antigen-driven T-cell expansion and shared usage of VβJβ TCR chains.
abstract: Autoimmune destruction of pancreatic islets in the nonobese diabetic (NOD) mouse is driven by T cells recognizing various autoantigens mostly in insulin-producing beta-cells. To investigate if T-cell accumulation in islets during early insulitis is clonally predetermined, we compared the complementarity determining regions (CDR3) of T-cell receptor (TCR)β-chains present in islet-infiltrating T cells in young prediabetic NOD mice. High-throughput sequencing of TCRβ-chain DNA extracted from islets of 7-wk old NOD mice revealed a biased TCRβ-chain repertoire in all mice, as a restricted number of clones (17-36 clones) was highly overrepresented and made over 20% of total islet repertoire in each mouse. Among these clones, various Vβ and Jβ families were present but certain VβJβ combinations such as TRBV19-0-TRBJ2-7 and TRBV13-3-TRBJ2-5 were highly shared between individual mice. On TCRβ-chain CDR sequence level, many islet clones (72-146) were shared between at least two individual mice. None of them was among expanded clones in both, suggesting considerable stochasticity in the interactions between TCR and peptide-MHC, even with a limited range of autoantigens. A comparison of islet-CDR3-sequences with CRD-sequences from other tissues revealed clonal overlap with pancreatic lymph node and gut, but these repertoires did not overlap together. Our results suggest that antigen-specific T cells are expanded in pancreatic lymph node and islets, but different specificities expand in individual mice. Some islet-infiltrating T-cell specificities may have a distinct origin shared with gut-infiltrating T cells.
authors.affiliation: Department of Medical Microbiology and Immunology, University of Turku, Turku, Finland.
authors.forename: R
authors.initials: R
authors.lastname: Toivonen
authors.affiliation: Haartman Institute and Research Programs Unit, Immunobiology, University of Helsinki, Helsinki, Finland.
authors.forename: T P
authors.initials: TP
authors.lastname: Arstila
authors.affiliation: Department of Medical Microbiology and Immunology, University of Turku, Turku, Finland. Electronic address: arno.hanninen@utu.fi.
authors.forename: A
authors.initials: A
authors.lastname: Hänninen
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001324:Autoantigens / Q000276:immunology*; D049109:Cell Proliferation; D002999:Clone Cells; D022801:Complementarity Determining Regions / Q000737:chemistry* / Q000276:immunology; D005260:Female; D007082:Ileum / Q000473:pathology; D007515:Islets of Langerhans / Q000276:immunology*; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology; D016688:Mice, Inbred NOD; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000276:immunology; D011236:Prediabetic State / Q000097:blood / Q000276:immunology* / Q000473:pathology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000737:chemistry* / Q000235:genetics; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology
chemical_list: D001324:Autoantigens; D022801:Complementarity Determining Regions; D010455:Peptides; D016693:Receptors, Antigen, T-Cell, alpha-beta
keywords: Antigen-driven expansion; Insulin-dependent diabetes mellitus; Nonobese diabetic mice; T-cell repertoire; VβCDR3 sequencing