Following the Fate of One Insulin-Reactive CD4 T cell
Conversion Into Teffs and Tregs in the Periphery Controls Diabetes in NOD Mice
- Georgia Fousteri1,
- Jean Jasinski2,
- Amy Dave1,
- Maki Nakayama2,
- Philippe Pagni1,
- Florence Lambolez1,
- Therese Juntti1,
- Ghanashyam Sarikonda1,
- Yang Cheng1,
- Michael Croft1,
- Hilde Cheroutre1,
- George Eisenbarth2⇓ and
- Matthias von Herrath1⇓
- 1Type 1 Diabetes Center, La Jolla Institute for Allergy and Immunology, La Jolla, California
- 2Barbara Davis Center for Childhood Diabetes, School of Medicine, University of Colorado, Denver, Colorado
- Corresponding author: George Eisenbarth, , or Matthias von Herrath, .
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.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db11-0671/-/DC1.
J.J. is currently affiliated with Partek, Inc., Chesterfield, Missouri.
- Received May 20, 2011.
- Accepted January 11, 2012.
- © 2012 by the American Diabetes Association.
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