PPARγ controls effector T cell functions to prevent autoimmunity in gender different way (BA4P.135)

Abstract Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor that regulates lipid and glucose homeostasis. Although several studies have demonstrated the intrinsic roles of PPARγ in adaptive immunity, its regulatory functions in T cells are not fully elucidated and controversial. We investigated the role of PPARγ in effector T cell functions in CD4-PPARγKO mice and analyzed the mice phenotype. Interestingly, mild autoimmune phenotypes with increase of follicular helper T cells, germinal centers, and auto-antibody production were found in female CD4-PPARγKO mice, however the male mice did not show any significant phenotypes. Whereas female PPARγ-deficient T cells were hyper-reactive to TcR stimulation to produce more cytokines and to proliferate vigorously, the male PPARγ-deficient T cells produced less or comparable cytokines. This gender different response might be due to the decreased expression of Bcl-2 and IL-7Rα in male PPARγ-deficient T cells, and diminished estrogen receptors (ERs) expression in female PPARγ-deficient T cells. Additionally, PPARγ agonist pioglitazone treatment showed selective inhibition on male Th17 cells while it showed pan-decrease of all effector T cell differentiation including female Th1, Th2, and Th17 cells. Collectively, these results suggest that PPARγ has a gender difference in the regulation of effector T cell functions and suggest different strategy is needed for the autoimmune therapeutics for specific gender.