IL-2 reverses established type 1 diabetes in NOD mice by a local effect on pancreatic regulatory T cells

Author:

Grinberg-Bleyer Yenkel111,Baeyens Audrey111,You Sylvaine2,Elhage Rima111,Fourcade Gwladys111,Gregoire Sylvie111,Cagnard Nicolas2,Carpentier Wassila3,Tang Qizhi4,Bluestone Jeffrey4,Chatenoud Lucienne2,Klatzmann David1115,Salomon Benoît L.111,Piaggio Eliane111

Affiliation:

1. Université Pierre et Marie Curie Univ Paris 06, Centre National de la Recherche Scientifique, UMR 7211, and Institut National de la Santé et de la Recherche Médicale (INSERM), U 959, Immunology-Immunopathology-Immunotherapy (I3), 75013 Paris, France

2. INSERM U580 and Bioinformatics Platform, Faculty of Medicine Paris Descartes, Hôpital Necker-Enfants Malades, 75015 Paris, France

3. Plate-forme Post-Génomique P3S, UPMC Univ Paris 6, Faculty of Medicine, 75013 Paris, France

4. Diabetes Center and the Department of Medicine, University of California, San Francisco, San Francisco, CA 94143

5. Department of Biotherapies, AP-HP, Hôpital Pitié-Salpetrière, 75013 Paris, France

Abstract

Regulatory T cells (T reg cells) play a major role in controlling the pathogenic autoimmune process in type 1 diabetes (T1D). Interleukin 2 (IL-2), a cytokine which promotes T reg cell survival and function, may thus have therapeutic efficacy in T1D. We show that 5 d of low-dose IL-2 administration starting at the time of T1D onset can reverse established disease in NOD (nonobese diabetic) mice, with long-lasting effects. Low-dose IL-2 increases the number of T reg cells in the pancreas and induces expression of T reg cell–associated proteins including Foxp3, CD25, CTLA-4, ICOS (inducible T cell costimulator), and GITR (glucocorticoid-induced TNF receptor) in these cells. Treatment also suppresses interferon γ production by pancreas-infiltrating T cells. Transcriptome analyses show that low-dose IL-2 exerts much greater influence on gene expression of T reg cells than effector T cells (T eff cells), suggesting that nonspecific activation of pathogenic T eff cells is less likely. We provide the first preclinical data showing that low-dose IL-2 can reverse established T1D, suggesting that this treatment merits evaluation in patients with T1D.

Publisher

Rockefeller University Press

Subject

Immunology,Immunology and Allergy

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