Gender-specific differences in PPARγ regulation of follicular helper T cell responses with estrogen

Peroxisome proliferator-activated receptor gamma (PPARγ), a master regulator of adipocyte differentiation, has recently been connected with effector T cells, though its role is still not clear. Here, we investigated the roles of PPARγ in follicular helper T (T(FH)) cell responses regarding gender specificity. NP-OVA immunization in female but not male CD4-PPARγ(KO) mice induced higher proportions of T(FH) cells and germinal center (GC) B cells following immunization than were seen in wild type mice. Treatment with the PPARγ agonist pioglitazone significantly reduced T(FH) cell responses in female mice while pioglitazone and estradiol (E2) co-treatment ameliorated T(FH) cells and GC responses in male mice. E2 treatment significantly enhanced PPARγ expression in male T cells, while T cell activation in the estrus but not in the diestrus stage of the menstrual cycle of females was inhibited by pioglitazone, suggesting that an estrogen-sufficient environment is important for PPARγ-mediated T cell regulation. These results demonstrate gender-based differences in sensitivities of PPARγ in T(FH) responses. These findings suggest that appropriate function of PPARγ is required in the regulation of female GC responses and that therapeutic strategies for autoimmune diseases using PPARγ agonists need to be tailored accordingly.