title: Proinsulin Expression Shapes the TCR Repertoire but Fails to Control the Development of Low-Avidity Insulin-Reactive CD8+ T Cells.
abstract: NOD mice, a model strain for human type 1 diabetes, express proinsulin (PI) in the thymus. However, insulin-reactive T cells escape negative selection, and subsequent activation of the CD8(+) T-cell clonotype G9C8, which recognizes insulin B15-23 via an αβ T-cell receptor (TCR) incorporating TRAV8-1/TRAJ9 and TRBV19/TRBJ2-3 gene rearrangements, contributes to the development of diabetes. In this study, we used fixed TRAV8-1/TRAJ9 TCRα-chain transgenic mice to assess the impact of PI isoform expression on the insulin-reactive CD8(+) T-cell repertoire. The key findings were: 1) PI2 deficiency increases the frequency of insulin B15-23-reactive TRBV19(+)CD8(+) T cells and causes diabetes; 2) insulin B15-23-reactive TRBV19(+)CD8(+) T cells are more abundant in the pancreatic lymph nodes of mice lacking PI1 and/or PI2; 3) overexpression of PI2 decreases TRBV19 usage in the global CD8(+) T-cell compartment; 4) a biased repertoire of insulin-reactive CD8(+) T cells emerges in the periphery regardless of antigen exposure; and 5) low-avidity insulin-reactive CD8(+) T cells are less affected by antigen exposure in the thymus than in the periphery. These findings inform our understanding of the diabetogenic process and reveal new avenues for therapeutic exploitation in type 1 diabetes.
authors.affiliation: Diabetes Research Group, Division of Infection and Immunity, School of Medicine, Cardiff University, Wales, U.K.
authors.forename: James A
authors.initials: JA
authors.lastname: Pearson
authors.affiliation: Diabetes Research Group, Division of Infection and Immunity, School of Medicine, Cardiff University, Wales, U.K.
authors.forename: Terri C
authors.initials: TC
authors.lastname: Thayer
authors.affiliation: Cellular Immunology Group, Division of Infection and Immunity, School of Medicine, Cardiff University, Wales, U.K.
authors.forename: James E
authors.initials: JE
authors.lastname: McLaren
authors.affiliation: Cellular Immunology Group, Division of Infection and Immunity, School of Medicine, Cardiff University, Wales, U.K.
authors.forename: Kristin
authors.initials: K
authors.lastname: Ladell
authors.affiliation: Diabetes Research Group, Division of Infection and Immunity, School of Medicine, Cardiff University, Wales, U.K.
authors.forename: Evy
authors.initials: E
authors.lastname: De Leenheer
authors.affiliation: Diabetes Research Group, Division of Infection and Immunity, School of Medicine, Cardiff University, Wales, U.K.
authors.forename: Amy
authors.initials: A
authors.lastname: Phillips
authors.affiliation: Diabetes Research Group, Division of Infection and Immunity, School of Medicine, Cardiff University, Wales, U.K.
authors.forename: Joanne
authors.initials: J
authors.lastname: Davies
authors.affiliation: Diabetes Research Group, Division of Infection and Immunity, School of Medicine, Cardiff University, Wales, U.K.
authors.forename: Dimitri
authors.initials: D
authors.lastname: Kakabadse
authors.affiliation: Cellular Immunology Group, Division of Infection and Immunity, School of Medicine, Cardiff University, Wales, U.K.
authors.forename: Kelly
authors.initials: K
authors.lastname: Miners
authors.affiliation: Cardiff Business School, Cardiff University, Wales, U.K.
authors.forename: Peter
authors.initials: P
authors.lastname: Morgan
authors.affiliation: Section of Endocrinology, School of Medicine, Yale University, New Haven, CT.
authors.forename: Li
authors.initials: L
authors.lastname: Wen
authors.affiliation: Cellular Immunology Group, Division of Infection and Immunity, School of Medicine, Cardiff University, Wales, U.K.
authors.forename: David A
authors.initials: DA
authors.lastname: Price
authors.affiliation: Diabetes Research Group, Division of Infection and Immunity, School of Medicine, Cardiff University, Wales, U.K. wongfs@cardiff.ac.uk.
authors.forename: F Susan
authors.initials: FS
authors.lastname: Wong
mesh_terms: D000818:Animals; D000915:Antibody Affinity; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D011384:Proinsulin / Q000378:metabolism*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology / Q000378:metabolism*
chemical_list: D007328:Insulin; D016693:Receptors, Antigen, T-Cell, alpha-beta; D011384:Proinsulin