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.
View: Text | PDF
Research Article Article has an altmetric score of 8

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

×

Figure 5

The Teff→Treg boost is not mediated by IL-2.

Options: View larger image (or click on image) Download as PowerPoint
The Teff→Treg boost is not mediated by IL-2. (A) Ins-HA mice were transf...
(A) Ins-HA mice were transferred with CFSE-labeled Thy-1.1+ expanded HA-Tregs alone or coinjected with preactivated HA-Teffs from IL-2–deficient or IL-2–sufficient littermate control mice. Divided HA-Treg numbers (CFSEdimCD4+Thy-1.1+ cells) were quantified in PLNs 10 days later. Dots represent individual mice, and bars show the means from at least 2 independent experiments. ***P < 0.0001. (B) Ins-HA mice were transferred with CFSE-labeled Thy-1.1+ expanded HA-Tregs alone or coinjected with IL-2–sufficient HA-Teffs. Phosphorylation of STAT5 on donor Tregs (CD4+Thy-1.1+FoxP3+) was determined at the indicated times in the PLN. Top panels show representative data from 2 independent experiments. Horizontal and vertical lines delineate positive p-STAT5 staining and undivided cells, respectively. At 96 hours, some mice were injected with 250,000 IU of human IL-2 3 hours before sacrifice as a positive control for phosphorylated STAT5 staining (right panel). The bottom graph represents the mean of 1 to 3 mice per time point from 2 independent experiments. (C and D) Ins-HA mice were transferred with CFSE-labeled Thy-1.1+ expanded HA-Tregs alone or coinjected with preactivated HA-Teffs. Various doses of anti–IL-2 mAb (S4B6 mAb, expressed in μl of ascites) were administered to block IL-2 after cell transfer. 10 days later, percentage of divided cells among donor Tregs (C) as well as percentages of whole donor Tregs (black circles) and endogenous Tregs (white squares) (D) were quantified in PLNs. Representative data of 2 independent experiments with 2 or 3 mice per group. Error bars represent SD.