Opposing roles of STAT1 and STAT3 in IL-21 function in CD4⁺ T cells

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 112; no. 30; pp. 9394 - 9399
• Main Authors: Wan, Chi-Keung, Andraski, Allison B., Spolski, Rosanne, Li, Peng, Kazemian, Majid, Oh, Jangsuk, Samsel, Leigh, Swanson, Phillip A., McGavern, Dorian B., Sampaio, Elizabeth P., Freeman, Alexandra F., Milner, Joshua D., Holland, Steven M., Leonard, Warren J.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 28.07.2015; National Acad Sciences
• Subjects: Animals; Biological Sciences; CD4-positive T-lymphocytes; CD4-Positive T-Lymphocytes - cytology; CD4-Positive T-Lymphocytes - immunology; Cell Differentiation; Cell Nucleus - metabolism; Cells; Chromatin Immunoprecipitation; Cytokines; Cytokines - immunology; Flow Cytometry; gain-of-function mutation; Gene expression; Gene Expression Regulation; genes; Immunoglobulin E - immunology; interferon-gamma; Interferon-gamma - immunology; interleukin-21; Interleukins - immunology; Lymphocytic Choriomeningitis - immunology; Lymphocytic choriomeningitis virus; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; patients; Phosphorylation; Sequence Analysis, RNA; Signal Transduction; STAT1 Transcription Factor - metabolism; STAT3 Transcription Factor - metabolism; T cell receptors; T-Box Domain Proteins - metabolism; transcription factors; IFN-γ; AD-HIES; T cells; IL-21; STATs
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1511711112

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 inStat3-deficient CD4⁺ T cells. RNA-Seq analysis of CD4⁺ T cells fromStat1-andStat3-deficient mice revealed that both STAT1 and STAT3 are critical for IL-21–mediated gene regulation. Expression of some genes, includingTbx21andIfng, was differentially regulated by STAT1 and STAT3. Moreover, opposing actions of STAT1 and STAT3 on IFN-γexpression in CD4⁺ T cells were demonstrated in vivo during chronic lymphocytic choriomeningitis infection. Finally, IL-21–mediated induction of STAT1 phosphorylation, as well asIFNGandTBX21expression, 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.