title: Autoantigen-induced focusing of Vβ13+ T cells precedes onset of autoimmune diabetes in the LEW.1WR1 rat.
abstract: The earliest events leading to autoimmune type 1 diabetes (T1D) are not known in any species. A T-cell receptor (TCR)-variable region, TCR-Vβ13, is required for susceptibility to autoimmune diabetes in rats, and selective depletion of Vβ13(+) T cells with an allele-specific monoclonal antibody prevents disease in multiple rat strains. To investigate the role of Vβ13 early in diabetes, we examined islet T-cell transcripts in susceptible (LEW.1WR1) and resistant (LEW.1W and Wistar Furth) strains induced with polyinosinic:polycytidylic acid. Vβ13(+) T cells displayed antigenic focusing in LEW.1WR1 islets 5 days postinduction and were characterized by a substantial decrease in complementarity determining region 3 diversity. This occurred prior to significant islet T-cell accumulation (day 7) or frank diabetes (days 10-14). Vβ13(+) transcripts increased in LEW.1WR1 islets during diabetes progression, but not in resistant rats. We also analyzed transcript clonality of rat TCR-Vα5, an ortholog of the dominant TCR-Vα chain found on insulin B:9-23-reactive T cells in nonobese diabetic rat islets. We observed clonal expansion of Vα5(+) transcripts in prediabetic LEW.1WR1 islets, suggesting that rat Vα5 is also an important component of islet autoantigen recognition. These data provide additional evidence that genome-encoded TCR sequences are important determinants of genetic susceptibility to T1D.
authors.affiliation: Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA.
authors.forename: Ryan A
authors.initials: RA
authors.lastname: Eberwine
authors.forename: Laura
authors.initials: L
authors.lastname: Cort
authors.forename: Michael
authors.initials: M
authors.lastname: Habib
authors.forename: John P
authors.initials: JP
authors.lastname: Mordes
authors.forename: Elizabeth P
authors.initials: EP
authors.lastname: Blankenhorn
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D030801:Animals, Genetically Modified; D000911:Antibodies, Monoclonal; D001324:Autoantigens; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000276:immunology*; D020022:Genetic Predisposition to Disease; D007515:Islets of Langerhans / Q000166:cytology; D011070:Poly I-C; D051381:Rats; D011919:Rats, Inbred Strains; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016176:T-Lymphocyte Subsets / Q000502:physiology*; D015854:Up-Regulation
chemical_list: D000911:Antibodies, Monoclonal; D001324:Autoantigens; D016693:Receptors, Antigen, T-Cell, alpha-beta; D011070:Poly I-C