PPAR gamma, T-Lymphocytes, Autoimmune Diseases
Biology | Ecology and Evolutionary Biology
Peroxisome proliferator-activated receptor gamma (PPARγ) is a transcription factor that regulates lipid and glucose metabolism. Although studies of PPARγ 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- PPARγ KO mice to investigate PPARγ -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 IκΒα, Sirt1, and Foxo1, which are inhibitors of NF-κΒ, was observed in PPARγ-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- PPARγ 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- PPARγ KO mice and the T cells showed increased of Βcl-6 and IL-21 expression suggesting its regulatory role in germinal center reaction. Collectively, these results suggest that PPARγ has a regulatory role for TFH cells and germinal center reaction to prevent autoimmunity.
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Park, Hong-Jai; Kim, Do-Hyun; Choi, Jin-Young; Kim, Won-Ju; Kim, Ji Yun; Senejani, Ali; Hwang, Soo Seok; Kim, Lark Kyun; Tobiasova, Zuzana; Lee, Gap Ryol; Craft, Joseph; Bothwell, Alfred L.M.; and Choi, Je-Min, "PPARγ Negatively Regulates T Cell Activation to Prevent Follicular Helper T Cells and Germinal Center Formation" (2014). Biology and Environmental Science Faculty Publications. 44.
Park H.J., Kim D.H., Choi J.Y., Kim W.J., Kim J.Y., Senejani A.G., Hwang S.S., Kim, L.K., Tobiasova Z., Lee G.R., Craft J., Choi J., Bothwell A.L., Choi J.M. “PPARγ negatively regulates T cell activation to prevent follicular helper T cells and germinal center formation.” PLoS One 2014 June 12;9(6) http://journals.plos.org/plosgenetics/article?id=10.1371/journal.pone.0099127