Following the fate of one insulin-reactive CD4 T cell: Conversion into Teffs and Tregs in the periphery controls diabetes in NOD mice

Georgia Fousteri, Jean Jasinski, Amy Dave, Maki Nakayama, Philippe Pagni, Florence Lambolez, Therese Juntti, Ghanashyam Sarikonda, Yang Cheng, Michael Croft, Hilde Cheroutre, George Eisenbarth, Matthias Von Herrath

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)1169-1179
Number of pages11
JournalDiabetes
Volume61
Issue number5
DOIs
Publication statusPublished - May 2012

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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    Fousteri, G., Jasinski, J., Dave, A., Nakayama, M., Pagni, P., Lambolez, F., Juntti, T., Sarikonda, G., Cheng, Y., Croft, M., Cheroutre, H., Eisenbarth, G., & Von Herrath, M. (2012). Following the fate of one insulin-reactive CD4 T cell: Conversion into Teffs and Tregs in the periphery controls diabetes in NOD mice. Diabetes, 61(5), 1169-1179. https://doi.org/10.2337/db11-0671