title: STAT3 protein promotes T-cell survival and inhibits interleukin-2 production through up-regulation of Class O Forkhead transcription factors.
abstract: Much is known about the role of STAT3 in regulating differentiation of interleukin-17-producing Th17 cells, but its function in other lymphocyte subsets is not well understood. In this report, we reveal wide-ranging functions of STAT3 in T-cells and provide evidence that STAT3 is convergence point for mechanisms that regulate lymphocyte quiescence and those controlling T-cell activation and survival. We show here that STAT3 inhibits T-lymphocyte proliferation by up-regulating the expression of Class-O Forkhead transcription factors, which play essential roles in maintaining T-cells in quiescent state. We further show that STAT3 binds directly to FoxO1 or FoxO3a promoter and that STAT3-deficiency resulted in down-regulation of the expression of FoxO1, FoxO3a and FoxO-target genes (IκB and p27Kip1). Compared with wild-type T-cells, STAT3-deficient T-cells produced more IL-2, due in part, to marked decrease in IκB-mediated sequestration of NF-κB in the cytoplasm and resultant enhancement of NF-κB activation. However, the high level of IL-2 production by STAT3-deficient T-cells was partially restored to normal levels by overexpressing FoxO1. It is notable that their exaggerated increase in IL-2 production rendered STAT3-deficient lymphocytes more susceptible to activation-induced cell death, suggesting that STAT3 might protect T-cells from apoptosis by limiting their production of IL-2 through up-regulation of FoxO1/FoxO3a expression. Moreover, we found that STAT3 enhanced survival of activated T-cells by up-regulating OX-40 and Bcl-2 while down-regulating FasL and Bad expression, suggesting that similar to role of FoxOs in regulating the lifespan of worms, STAT3 and FoxO pathways converge to regulate lifespan of T-lymphocytes.
authors: Molecular Immunology Section, Laboratory of Immunology, NEI, National Institutes of Health, Bethesda, Maryland 20892.
authors: Hyun-Mee
authors: HM
authors: Oh
authors: Molecular Immunology Section, Laboratory of Immunology, NEI, National Institutes of Health, Bethesda, Maryland 20892.
authors: Cheng-Rong
authors: CR
authors: Yu
authors: Department of Biochemistry and Molecular & Cellular Biology, Georgetown University School of Medicine, Washington, D.C. 20057.
authors: Nady
authors: N
authors: Golestaneh
authors: Molecular Immunology Section, Laboratory of Immunology, NEI, National Institutes of Health, Bethesda, Maryland 20892.
authors: Ahjoku
authors: A
authors: Amadi-Obi
authors: Molecular Immunology Section, Laboratory of Immunology, NEI, National Institutes of Health, Bethesda, Maryland 20892.
authors: Yun Sang
authors: YS
authors: Lee
authors: Department of Biomedical Engineering, Harvard College, Harvard University, Cambridge, Massachusetts 02138.
authors: Amarachi
authors: A
authors: Eseonu
authors: Molecular Immunology Section, Laboratory of Immunology, NEI, National Institutes of Health, Bethesda, Maryland 20892.
authors: Rashid M
authors: RM
authors: Mahdi
authors: Molecular Immunology Section, Laboratory of Immunology, NEI, National Institutes of Health, Bethesda, Maryland 20892. Electronic address: egwuaguc@nei.nih.gov.
authors: Charles E
authors: CE
authors: Egwuagu
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology; D016207:Cytokines / Q000378:metabolism; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D007376:Interleukin-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000737:chemistry / Q000502:physiology*; D013601:T-Lymphocytes / Q000378:metabolism*; D058504:Th17 Cells / Q000166:cytology; D015854:Up-Regulation
chemical_list: D016207:Cytokines; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; C467200:Foxo1 protein, mouse; D007376:Interleukin-2; D007378:Interleukins; D016328:NF-kappa B; D050796:STAT3 Transcription Factor