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 6

Tregs boosted in vitro by Teffs change their phenotype.

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Tregs boosted in vitro by Teffs change their phenotype. (A) Expanded CFS...
(A) Expanded CFSE-labeled Thy-1.1+ HA-Tregs were cultured for 5 supplemental days with IL-2–sufficient or –deficient HA-pulsed DCs alone or with freshly-purified IL-2–sufficient or –deficient HA-Teffs, in the presence or not of IL-2. Representative CFSE profile of CD4+Thy-1.1+ Tregs out of 3 independent experiments. (B and C) Comparison of the transcriptome of expanded HA-Tregs after 5 days of culture with IL-2, HA-pulsed DCs in the presence (boosted Tregs) or absence (nonboosted Tregs) of IL-2–sufficient Teffs. (B) Scatter plot comparison of average expression values in boosted Treg versus nonboosted Treg for all the 45,282 probes. Threshold lines were drawn at 1.5–fold-change expression (P ≤ 0.05), and significant probes were depicted as bold spots. Genes of interest are indicated by their symbol names. (C) Heat map of distinct expression profiles revealed by microarray analysis of the nonboosted (biological samples 1 and 2) and boosted Treg populations (samples 3 and 4). Apostrophes indicate technical replicates of each biological sample. The genes were selected based on a fold-change ≥ 2 (P ≤ 0.05). A color code scale indicates fold-change variation. (D) Tregs were cultured for 5 days as in B. Expression of the indicated molecules was compared when Tregs were cultivated with or without HA-Teffs. Histograms are representative of 2 independent experiments.