title: Following the fate of one insulin-reactive CD4 T cell: conversion into Teffs and Tregs in the periphery controls diabetes in NOD mice.
abstract: In diabetic patients and susceptible mice, insulin is a targeted autoantigen. Insulin B chain 9-23 (B:9-23) autoreactive CD4 T cells are key for initiating autoimmune diabetes in NOD mice; however, little is known regarding their origin and function. To this end, B:9-23-specific, BDC12-4.1 T-cell receptor (TCR) transgenic (Tg) mice were studied, of which, despite expressing a single TCR on the recombination activating gene-deficient background, only a fraction develops diabetes in an asynchronous manner. BDC12-4.1 CD4 T cells convert into effector (Teff) and Foxp3(+)-expressing adaptive regulatory T cells (aTregs) soon after leaving the thymus as a result of antigen recognition and homeostatic proliferation. The generation of aTreg causes the heterogeneous diabetes onset, since crossing onto the scurfy (Foxp3) mutation, BDC12-4.1 TCR Tg mice develop accelerated and fully penetrant diabetes. Similarly, adoptive transfer and bone marrow transplantation experiments showed differential diabetes kinetics based on Foxp3(+) aTreg's presence in the BDC12-4.1 donors. A single-specificity, insulin-reactive TCR escapes thymic deletion and simultaneously converts into aTreg and Teff, establishing an equilibrium that determines diabetes penetrance. These results are of particular importance for understanding disease pathogenesis. They suggest that once central tolerance is bypassed, autoreactive cells arriving in the periphery do not by default follow solely a pathogenic fate upon activation.
authors.affiliation: Type 1 Diabetes Center, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors.forename: Georgia
authors.initials: G
authors.lastname: Fousteri
authors.forename: Jean
authors.initials: J
authors.lastname: Jasinski
authors.forename: Amy
authors.initials: A
authors.lastname: Dave
authors.forename: Maki
authors.initials: M
authors.lastname: Nakayama
authors.forename: Philippe
authors.initials: P
authors.lastname: Pagni
authors.forename: Florence
authors.initials: F
authors.lastname: Lambolez
authors.forename: Therese
authors.initials: T
authors.lastname: Juntti
authors.forename: Ghanashyam
authors.initials: G
authors.lastname: Sarikonda
authors.forename: Yang
authors.initials: Y
authors.lastname: Cheng
authors.forename: Michael
authors.initials: M
authors.lastname: Croft
authors.forename: Hilde
authors.initials: H
authors.lastname: Cheroutre
authors.forename: George
authors.initials: G
authors.lastname: Eisenbarth
authors.forename: Matthias
authors.initials: M
authors.lastname: von Herrath
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology*; D003920:Diabetes Mellitus / Q000517:prevention & control*; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D007328:Insulin / Q000494:pharmacology*; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D008285:Major Histocompatibility Complex; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D009154:Mutation; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000502:physiology
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007328:Insulin; D011948:Receptors, Antigen, T-Cell; D016753:Interleukin-10; D007371:Interferon-gamma