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

• Published in: The Journal of clinical investigation 2010-12, Vol.120 (12), p.4558-4568
• Main Authors: Grinberg-Bleyer, Yenkel, Saadoun, David, Baeyens, Audrey, Billiard, Fabienne, Goldstein, Jérémie D, Grégoire, Sylvie, Martin, Gaëlle H, Elhage, Rima, Derian, Nicolas, Carpentier, Wassila, Marodon, Gilles, Klatzmann, David, Piaggio, Eliane, Salomon, Benoît L
• Format: Article
• Language: English
• Subjects: Adoptive Transfer; Animals; Antigens; Autoimmune diseases; Autoimmunity; Biomedical research; Care and treatment; Diabetes; Diabetes Mellitus, Type 1 - genetics; Diabetes Mellitus, Type 1 - immunology; Diabetes Mellitus, Type 1 - prevention & control; Disease; Experiments; Feedback; Feedback, Physiological; Genotype & phenotype; Human health and pathology; Inflammation; Interleukin-2 - deficiency; Interleukin-2 - genetics; Interleukin-2 - metabolism; Islets of Langerhans - immunology; Life Sciences; Lymphocyte Activation; Lymphocyte Cooperation - immunology; Lymphocytes; Mice; Mice, Inbred BALB C; Mice, Inbred NOD; Mice, Knockout; Mice, Transgenic; Oligonucleotide Array Sequence Analysis; Physiological aspects; Properties; Receptors, Antigen, T-Cell - genetics; T cells; T-Lymphocyte Subsets - immunology; T-Lymphocytes, Helper-Inducer - immunology; T-Lymphocytes, Regulatory - immunology
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI42945

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.