PPAR[gamma] Negatively Regulates T Cell Activation to Prevent Follicular Helper T Cells and Germinal Center Formation

Peroxisome proliferator-activated receptor gamma (PPAR[gamma]) is a transcription factor that regulates lipid and glucose metabolism. Although studies of PPAR[gamma] ligands have demonstrated its regulatory functions in inflammation and adaptive immunity, its intrinsic role in T cells and autoimmunity has yet to be fully elucidated. Here we used CD4-PPAR[gamma].sup.KO mice to investigate PPAR[gamma]-deficient T cells, which were hyper-reactive to produce higher levels of cytokines and exhibited greater proliferation than wild type T cells with increased ERK and AKT phosphorylation. Diminished expression of I[kappa]B[alpha], Sirt1, and Foxo1, which are inhibitors of NF-[kappa]B, was observed in PPAR[gamma]-deficient T cells that were prone to produce all the signature cytokines under Th1, Th2, Th17, and Th9 skewing condition. Interestingly, 1-year-old CD4-PPAR[gamma].sup.KO mice spontaneously developed moderate autoimmune phenotype by increased activated T cells, follicular helper T cells (T.sub.FH cells) and germinal center B cells with glomerular inflammation and enhanced autoantibody production. Sheep red blood cell immunization more induced T.sub.FH cells and germinal centers in CD4-PPAR[gamma].sup.KO mice and the T cells showed increased of Bcl-6 and IL-21 expression suggesting its regulatory role in germinal center reaction. Collectively, these results suggest that PPAR[gamma] has a regulatory role for T.sub.FH cells and germinal center reaction to prevent autoimmunity.