title: PDCD5 negatively regulates autoimmunity by upregulating FOXP3(+) regulatory T cells and suppressing Th17 and Th1 responses.
abstract: Maintenance of FOXP3 protein expression is crucial for differentiation and maturation of regulatory T (Treg) cells, which play important roles in immune homeostasis and immune tolerance. We demonstrate here that PDCD5 interacts with FOXP3, increases acetylation of FOXP3 in synergy with Tip60 and enhances the repressive function of FOXP3. In PDCD5 transgenic (PDCD5tg) mice, overexpression of PDCD5 enhanced the level of FOXP3 protein and percentage of CD4(+)CD25(+)FOXP3(+) cells. Naïve CD4(+) T cells from PDCD5tg mice were more sensitive to TGF-β-induced Treg polarization and expansion. These induced Tregs retained normal suppressive function in vitro. Severity of experimentally-induced autoimmune encephalomyelitis (EAE) in PDCD5tg mice was significantly reduced relative to that of wild-type mice. The beneficial effect of PDCD5 likely resulted from increases of Treg cell frequency, accompanied by a reduction of the predominant pathogenic Th17/Th1 response. Activation-induced cell death enhanced by PDCD5 was also linked to this process. This is the first report revealing that PDCD5 activity in T cells suppresses autoimmunity by modulating Tregs. This study suggests that PDCD5 serves as a guardian of immunological functions and that the PDCD5-FOXP3-Treg axis may be a therapeutic target for autoimmunity.
authors.affiliation: Key Laboratory of Medical Immunology, Ministry of Health, Peking University Health Science Center, Beijing 100191, China; Peking University Center for Human Disease Genomics, Peking University, Beijing 100191, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Xiao
authors.forename: Chen
authors.initials: C
authors.lastname: Liu
authors.forename: Ge
authors.initials: G
authors.lastname: Li
authors.forename: Saihui
authors.initials: S
authors.lastname: Peng
authors.forename: Jia
authors.initials: J
authors.lastname: Hu
authors.forename: Liujing
authors.initials: L
authors.lastname: Qu
authors.forename: Ping
authors.initials: P
authors.lastname: Lv
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.forename: Dalong
authors.initials: D
authors.lastname: Ma
authors.forename: Yingyu
authors.initials: Y
authors.lastname: Chen
mesh_terms: D000107:Acetylation; D000818:Animals; D017209:Apoptosis / Q000276:immunology; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D015551:Autoimmunity / Q000276:immunology*; D015704:CD4 Antigens / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D002460:Cell Line; D049109:Cell Proliferation; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000628:therapy; D005260:Female; D051858:Forkhead Transcription Factors / Q000276:immunology / Q000378:metabolism; D057809:HEK293 Cells; D051548:Histone Acetyltransferases / Q000235:genetics / Q000276:immunology; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D018655:Lymphocyte Count; D000074443:Lysine Acetyltransferase 5; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009103:Multiple Sclerosis / Q000276:immunology / Q000628:therapy; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D034622:RNA Interference; D034741:RNA, Small Interfering; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology*; D015534:Trans-Activators / Q000235:genetics / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000276:immunology
chemical_list: D051017:Apoptosis Regulatory Proteins; D015704:CD4 Antigens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D009363:Neoplasm Proteins; C486488:Pdcd5 protein, mouse; D034741:RNA, Small Interfering; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D051548:Histone Acetyltransferases; C523065:Kat5 protein, mouse; D000074443:Lysine Acetyltransferase 5
keywords: Experimental autoimmune encephalomyelitis; FOXP3; PDCD5; Regulatory T cells