Pathogenic T cells have a paradoxical protective effect in murine autoimmune diabetes by boosting Tregs
Yenkel Grinberg-Bleyer, … , Eliane Piaggio, Benoît L. Salomon
Yenkel Grinberg-Bleyer, … , Eliane Piaggio, Benoît L. Salomon
Published November 22, 2010
Citation Information: J Clin Invest. 2010;120(12):4558-4568. https://doi.org/10.1172/JCI42945.
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Research Article

Pathogenic T cells have a paradoxical protective effect in murine autoimmune diabetes by boosting Tregs

Abstract

CD4+CD25+Foxp3+ Tregs play a major role in prevention of autoimmune diseases. The suppressive effect of Tregs on effector T cells (Teffs), the cells that can mediate autoimmunity, has been extensively studied. However, the in vivo impact of Teff activation on Tregs during autoimmunity has not been explored. In this study, we have shown that CD4+ Teff activation strongly boosts the expansion and suppressive activity of Tregs. This helper function of CD4+ T cells, which we believe to be novel, was observed in the pancreas and draining lymph nodes in mouse recipients of islet-specific Teffs and Tregs. Its physiological impact was assessed in autoimmune diabetes. When islet-specific Teffs were transferred alone, they induced diabetes. Paradoxically, when the same Teffs were cotransferred with islet-specific Tregs, they induced disease protection by boosting Treg expansion and suppressive function. RNA microarray analyses suggested that TNF family members were involved in the Teff-mediated Treg boost. In vivo experiments showed that this Treg boost was partially dependent on TNF but not on IL-2. This feedback regulatory loop between Teffs and Tregs may be critical to preventing or limiting the development of autoimmune diseases.

Authors

Yenkel Grinberg-Bleyer, David Saadoun, Audrey Baeyens, Fabienne Billiard, Jérémie D. Goldstein, Sylvie Grégoire, Gaëlle H. Martin, Rima Elhage, Nicolas Derian, Wassila Carpentier, Gilles Marodon, David Klatzmann, Eliane Piaggio, Benoît L. Salomon

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Figure 2

Paradoxical protective effect of diabetogenic T cells in autoimmune diabetes.

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Paradoxical protective effect of diabetogenic T cells in autoimmune diab...
(A) Diabetes incidence in ins-HA mice after transfer of freshly purified HA-Teffs (white circles, n = 13) or preactivated HA-Teffs (black circles, n = 9) or expanded HA-Tregs (white squares) or coinjection of preactivated HA-Teffs and expanded HA-Tregs (white triangles, n = 9). Data were from 4 experiments. (B) Ins-HA mice were transferred with expanded HA-Tregs alone (white squares, n = 12) or with preactivated HA-Teffs (white triangles, n = 21). 3 weeks later (arrow), mice were challenged for diabetes induction with preactivated HA-Teffs. Data were from 4 independent experiments. (C) Ins-HA mice were cotransferred with expanded HA-Tregs and the CD4+ (white triangles, n = 14) or CD4– (black diamonds, n = 12) fractions of preactivated HA-Teffs. Mice were challenged 3 weeks later (arrow) with preactivated HA-Teffs. Data were from 2 independent experiments. (D and E) Ins-HA mice were transferred with 20 × 106 expanded HA-Tregs alone (black squares, n = 4) or coinjected with 2 × 106 expanded HA-Tregs and 2 × 106 preactivated HA-Teffs (white triangles, n = 21) or injected with PBS only (for E). Mice were challenged 3 weeks later with preactivated HA-Teffs to test their susceptibility to diabetes induction (D) or with CFSE-labeled Thy-1.1+ preactivated HA-Teffs to analyze their activation 4 days later in PLNs (E). (E) CFSE profile and IFN-γ production of CD4+Thy-1.1+FoxP3– cells (left panels) and quantification of CD4+Thy-1.1+FoxP3–IFNγ+ cell numbers (right panel). In A–D, Teffs and Tregs were obtained from Thy-1.2 TCR-HA mice. Data were from 6 mice per group from 2 independent experiments. *P < 0.05; **P < 0.001. Error bars represent SD.