PPAR? negatively regulates T cell activation to prevent follicular helper T cells and germinal center formation.

ABSTRACT: Peroxisome proliferator-activated receptor gamma (PPAR?) is a transcription factor that regulates lipid and glucose metabolism. Although studies of PPAR? 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?KO mice to investigate PPAR?-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?B?, Sirt1, and Foxo1, which are inhibitors of NF-?B, was observed in PPAR?-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?KO mice spontaneously developed moderate autoimmune phenotype by increased activated T cells, follicular helper T cells (TFH cells) and germinal center B cells with glomerular inflammation and enhanced autoantibody production. Sheep red blood cell immunization more induced TFH cells and germinal centers in CD4-PPAR?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? has a regulatory role for TFH cells and germinal center reaction to prevent autoimmunity.

SUBMITTER: Park HJ 

PROVIDER: S-EPMC4055678 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature