title: Opposing roles of STAT1 and STAT3 in IL-21 function in CD4+ T cells.
abstract: IL-21 is a type I cytokine essential for immune cell differentiation and function. Although IL-21 can activate several STAT family transcription factors, previous studies focused mainly on the role of STAT3 in IL-21 signaling. Here, we investigated the role of STAT1 and show that STAT1 and STAT3 have at least partially opposing roles in IL-21 signaling in CD4(+) T cells. IL-21 induced STAT1 phosphorylation, and this was augmented in Stat3-deficient CD4(+) T cells. RNA-Seq analysis of CD4(+) T cells from Stat1- and Stat3-deficient mice revealed that both STAT1 and STAT3 are critical for IL-21-mediated gene regulation. Expression of some genes, including Tbx21 and Ifng, was differentially regulated by STAT1 and STAT3. Moreover, opposing actions of STAT1 and STAT3 on IFN-γ expression in CD4(+) T cells were demonstrated in vivo during chronic lymphocytic choriomeningitis infection. Finally, IL-21-mediated induction of STAT1 phosphorylation, as well as IFNG and TBX21 expression, were higher in CD4(+) T cells from patients with autosomal dominant hyper-IgE syndrome, which is caused by STAT3 deficiency, as well as in cells from STAT1 gain-of-function patients. These data indicate an interplay between STAT1 and STAT3 in fine-tuning IL-21 actions.
authors.affiliation: Laboratory of Molecular Immunology and Immunology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892-1674;
authors.forename: Chi-Keung
authors.initials: CK
authors.lastname: Wan
authors.affiliation: Laboratory of Molecular Immunology and Immunology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892-1674;
authors.forename: Allison B
authors.initials: AB
authors.lastname: Andraski
authors.affiliation: Laboratory of Molecular Immunology and Immunology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892-1674;
authors.forename: Rosanne
authors.initials: R
authors.lastname: Spolski
authors.affiliation: Laboratory of Molecular Immunology and Immunology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892-1674;
authors.forename: Peng
authors.initials: P
authors.lastname: Li
authors.affiliation: Laboratory of Molecular Immunology and Immunology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892-1674;
authors.forename: Majid
authors.initials: M
authors.lastname: Kazemian
authors.affiliation: Laboratory of Molecular Immunology and Immunology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892-1674;
authors.forename: Jangsuk
authors.initials: J
authors.lastname: Oh
authors.affiliation: Flow Cytometry Core, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892-1674;
authors.forename: Leigh
authors.initials: L
authors.lastname: Samsel
authors.affiliation: Viral Immunology and Intravital Imaging Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892-1674;
authors.forename: Phillip A
authors.initials: PA
authors.lastname: Swanson
authors.affiliation: Viral Immunology and Intravital Imaging Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892-1674;
authors.forename: Dorian B
authors.initials: DB
authors.lastname: McGavern
authors.affiliation: Laboratory of Clinical Infectious Diseases, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-1674;
authors.forename: Elizabeth P
authors.initials: EP
authors.lastname: Sampaio
authors.affiliation: Laboratory of Clinical Infectious Diseases, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-1674;
authors.forename: Alexandra F
authors.initials: AF
authors.lastname: Freeman
authors.affiliation: Laboratory of Allergic Diseases, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-1674.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Milner
authors.affiliation: Laboratory of Clinical Infectious Diseases, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-1674;
authors.forename: Steven M
authors.initials: SM
authors.lastname: Holland
authors.affiliation: Laboratory of Molecular Immunology and Immunology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892-1674; wjl@helix.nih.gov.
authors.forename: Warren J
authors.initials: WJ
authors.lastname: Leonard
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology; D002454:Cell Differentiation; D002467:Cell Nucleus / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D016207:Cytokines / Q000276:immunology; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D007073:Immunoglobulin E / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology; D007378:Interleukins / Q000276:immunology*; D008216:Lymphocytic Choriomeningitis / Q000276:immunology; D008217:Lymphocytic choriomeningitis virus; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D010766:Phosphorylation; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D017423:Sequence Analysis, RNA; D015398:Signal Transduction; D020825:T-Box Domain Proteins / Q000378:metabolism; D000098815:T-bet Transcription Factor; D000098546:Interleukin-21
chemical_list: D016207:Cytokines; D007378:Interleukins; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D007073:Immunoglobulin E; D007371:Interferon-gamma; D000098546:Interleukin-21
keywords: AD-HIES; IFN-γ; IL-21; STATs; T cells