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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 Article has an altmetric score of 8

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

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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 7

The Teff→Treg boost is TNF dependent.

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The Teff→Treg boost is TNF dependent.
(A–C) Four- to 6-week-old NOD mice...
(A–C) Four- to 6-week-old NOD mice were transferred with freshly isolated CFSE-labeled CD45.2+ BDC2.5-Tregs alone or coinjected with preactivated CD45.1+ BDC2.5-Teffs with or without TNFR2-Fc treatment. Representative CFSE profile (A) and absolute number of divided donor Tregs (CFSEdimCD4+CD45.2+FoxP3+ cells) in PLNs 5 days after transfer (B) from 6 independent experiments. Each symbol represents an individual mouse and bars show the means. (C) Relative accumulation of divided donor Tregs in the pancreas of TNFR2-Fc–treated mice compared with PBS-treated mice 5 days after transfer. Data are from 5 independent experiments with 6 mice per group. (D and E) Representative CFSE profile (D) and absolute number (E) of donor Teffs (CD4+CD45.2+FoxP3– cells) in PLNs 5 days after cotransfer of CD45.2+ Teffs and CD45.1+ Tregs in mice treated with saline or TNFR-Fc. (F) Ins-HA mice were injected with CFSE-labeled Thy-1.1+ expanded HA-Tregs alone or with preactivated HA-Teffs with or without TNFR-Fc treatment. Absolute numbers of divided donor Tregs (CFSEdimCD4+Thy-1.1+ cells) were quantified in PLNs at day 7 after cell transfer. Each symbol represents an individual mouse, and bars show the means pooled from 3 independent experiments. *P < 0.05; **P < 0.001. Error bars represent SD.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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