title: PPARγ negatively regulates T cell activation to prevent follicular helper T cells and germinal center formation.
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.
authors.affiliation: Department of Life Science, Research Institute for Natural Sciences, Hanyang University, Seoul, Korea; Hanyang Biomedical Research Institute, Seoul, Korea.
authors.forename: Hong-Jai
authors.initials: HJ
authors.lastname: Park
authors.affiliation: Department of Life Science, Research Institute for Natural Sciences, Hanyang University, Seoul, Korea; Hanyang Biomedical Research Institute, Seoul, Korea.
authors.forename: Do-Hyun
authors.initials: DH
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine (Rheumatology), Yale University School of Medicine, New Haven, Connecticut, United States of America.
authors.forename: Jin-Young
authors.initials: JY
authors.lastname: Choi
authors.affiliation: Department of Life Science, Research Institute for Natural Sciences, Hanyang University, Seoul, Korea; Hanyang Biomedical Research Institute, Seoul, Korea.
authors.forename: Won-Ju
authors.initials: WJ
authors.lastname: Kim
authors.affiliation: Department of Life Science, Research Institute for Natural Sciences, Hanyang University, Seoul, Korea; Hanyang Biomedical Research Institute, Seoul, Korea.
authors.forename: Ji Yun
authors.initials: JY
authors.lastname: Kim
authors.affiliation: Department of Therapeutic Radiology and Genetics, Yale University School of Medicine, New Haven, Connecticut, United States of America.
authors.forename: Alireza G
authors.initials: AG
authors.lastname: Senejani
authors.affiliation: Department of Life Science, Sogang University, Seoul, Korea.
authors.forename: Soo Seok
authors.initials: SS
authors.lastname: Hwang
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, United States of America.
authors.forename: Lark Kyun
authors.initials: LK
authors.lastname: Kim
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, United States of America.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Tobiasova
authors.affiliation: Department of Life Science, Sogang University, Seoul, Korea.
authors.forename: Gap Ryol
authors.initials: GR
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine (Rheumatology), Yale University School of Medicine, New Haven, Connecticut, United States of America; Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, United States of America.
authors.forename: Joseph
authors.initials: J
authors.lastname: Craft
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, United States of America.
authors.forename: Alfred L M
authors.initials: AL
authors.lastname: Bothwell
authors.affiliation: Department of Life Science, Research Institute for Natural Sciences, Hanyang University, Seoul, Korea; Hanyang Biomedical Research Institute, Seoul, Korea.
authors.forename: Je-Min
authors.initials: JM
authors.lastname: Choi
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D018858:Germinal Center / Q000276:immunology*; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D051560:Proto-Oncogene Proteins c-bcl-6; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*
chemical_list: C490010:Bcl6 protein, mouse; D016207:Cytokines; D004268:DNA-Binding Proteins; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D047495:PPAR gamma; D051560:Proto-Oncogene Proteins c-bcl-6; D051550:I-kappa B Kinase; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1