Abstract
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-PPARγKO 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 IκBα, Sirt1, and Foxo1, which are inhibitors of NF-κB, 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-PPARγKO 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-PPARγKO 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 PPARγ has a regulatory role for TFH cells and germinal center reaction to prevent autoimmunity.
Highlights
Nuclear receptors constitute a superfamily of ligand-dependent transcription factors that regulate diverse aspects of metabolism and homeostasis
Peroxisome proliferator-activated receptor gamma (PPARc)-deficiency did not affect the frequency of CD4+, CD8+, and Foxp3+ natural regulatory T cell in the thymus of 6- to 8-week-old mice (Figure S1A-D), the proportion of lymphocyte population including B cells, NK cells, and naıve or memory T cells in the spleen (Figure S1E-L)
These data suggest that PPARc deletion in CD4+ T cells does not affect thymic and splenic cell populations that PPARc is dispensable for T cell development
Summary
Nuclear receptors constitute a superfamily of ligand-dependent transcription factors that regulate diverse aspects of metabolism and homeostasis. This family is further subdivided into three subclasses based on their DNA-binding and ligand-binding properties, including classical steroid hormone receptors, adopted orphan receptors, and orphan receptors [1,2,3,4]. Peroxisome Proliferator-activated Receptors (PPAR) are emerging adopted orphan nuclear receptors that regulate lipid and glucose metabolism, as well as cell growth, differentiation, apoptosis, and immunity, in a wide variety of cells. Synthetic PPARc agonists called thiazolidinediones (TZD) improved insulin sensitivity in metabolic syndrome [5,8]. The PPARc agonist 15-deoxy-g12,14-prostaglandin J2 (15PGJ2) has been shown to downregulate T cell proliferation and IL-
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