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Opposing Roles of STAT1 and STAT3 in IL-21 Function in + CD4 T Cells

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Opposing Roles of STAT1 and STAT3 in IL-21 Function in + CD4 T Cells Opposing roles of STAT1 and STAT3 in IL-21 function in + CD4 T cells Chi-Keung Wana,1, Allison B. Andraskia,1,2, Rosanne Spolskia, Peng Lia, Majid Kazemiana, Jangsuk Oha, Leigh Samselb, Phillip A. Swanson IIc, Dorian B. McGavernc, Elizabeth P. Sampaiod, Alexandra F. Freemand, Joshua D. Milnere, Steven M. Hollandd, and Warren J. Leonarda,3 aLaboratory of Molecular Immunology and Immunology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892-1674; bFlow Cytometry Core, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892-1674; cViral Immunology and Intravital Imaging Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892-1674; dLaboratory of Clinical Infectious Diseases, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-1674; and eLaboratory of Allergic Diseases, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-1674 Contributed by Warren J. Leonard, June 18, 2015 (sent for review May 19, 2015; reviewed by Thomas R. Malek and Howard A. Young) + IL-21 is a type I cytokine essential for immune cell differentiation STAT1 to promote CD8 T-cell cytotoxicity and apoptosis of and function. Although IL-21 can activate several STAT family mantle cell lymphoma (16, 17). We now have elucidated the transcription factors, previous studies focused mainly on the role roles of STAT1 in IL-21 signaling and identified an interplay of STAT3 in IL-21 signaling. Here, we investigated the role of STAT1 between STAT1 and STAT3 in mediating the actions of IL-21 + and show that STAT1 and STAT3 have at least partially opposing in CD4 T cells, and have also found increased IL-21–mediated rolesinIL-21signalinginCD4+ T cells. IL-21 induced STAT1 phos- + induction of STAT1 phosphorylation in cells from patients with phorylation, and this was augmented in Stat3-deficient CD4 T + autosomal dominant hyper-IgE syndrome (AD-HIES), and in cells. RNA-Seq analysis of CD4 T cells from Stat1- and Stat3-de- patients with a STAT1 gain-of-function (GOF) mutation, which ficient mice revealed that both STAT1 and STAT3 are critical for IL- correlates with increased IFNG (interferon gamma) and TBX21 – 21 mediated gene regulation. Expression of some genes, including (T-box 21) expression after IL-21 stimulation. Tbx21 and Ifng, was differentially regulated by STAT1 and STAT3. Moreover, opposing actions of STAT1 and STAT3 on IFN-γ expression + Results in CD4 T cells were demonstrated in vivo during chronic lympho- IL-21 Induces Sustained STAT1 and STAT3 Activation in CD4+ T Cells. – cytic choriomeningitis infection. Finally, IL-21 mediated induction of IL-21 was previously shown to induce strong and sustained STAT3 STAT1 phosphorylation, as well as IFNG and TBX21 expression, were + phosphorylation (pSTAT3) but only weaker and more transient higher in CD4 T cells from patients with autosomal dominant hyper- STAT1 phosphorylation (pSTAT1) in total splenocytes, B cells, IgE syndrome, which is caused by STAT3 deficiency, as well as in cells + and CD8 T cells (18, 19). We first compared IL-21–induced from STAT1 gain-of-function patients. These data indicate an inter- + + play between STAT1 and STAT3 in fine-tuning IL-21 actions. pSTAT1 and pSTAT3 in preactivated CD4 and CD8 Tcells. IL-21 induced strong pSTAT1 and pSTAT3 at 30 min (Fig. 1 A IL-21 | T cells | STATs | IFN-γ | AD-HIES Significance nterleukin-21 (IL-21) is a type I cytokine that signals via a receptor composed of IL-21R and the common cytokine re- IL-21 is a type I cytokine important for immune cell differenti- I ation and function. We found that transcription factors STAT1 ceptor γ-chain, γc (1). γc is also shared by the receptors for IL-2, IL-4, IL-7, IL-9, and IL-15 and is mutated in humans with and STAT3 play partially opposing roles in IL-21 function in + – X-linked severe combined immunodeficiency (XSCID), a dis- CD4 T cells. Both STAT1 and STAT3 control IL-21 mediated gene regulation, with some genes, including Ifng, Tbx21, and ease characterized by the absence of T and natural killer (NK) γ cells and the presence of nonfunctional B cells (2). IL-21 is Il21 reciprocally regulated by these STATs. IFN- production + was also differentially regulated by these STATs in vitro during primarily produced by CD4 T cells and natural killer T (NKT) + CD4 T-cell differentiation and in vivo during chronic lympho- cells, but it has pleiotropic actions on both adaptive and innate cytic choriomeningitis infection. Importantly, IL-21–induced immune cells, including T, B, NK, NKT, and dendritic cells (1). + IFNG and TBX21 expression was higher in CD4 T cells from In T cells, IL-21 can act as a comitogen and cooperates with IL-7 + patients with autosomal dominant hyper-IgE syndrome or with and IL-15 to expand CD8 T cells (3), promotes Th17 differ- – STAT1 gain-of-function mutations, suggesting that dys-regu- entiation (4 6), and induces BCL6 expression (7) to promote T lated IL-21–STAT signaling partially explains the clinical mani- follicular helper cell development (8, 9). In B cells, IL-21 pro- festations of these patients. motes plasma cell differentiation (10, 11), and in combination with IL-4, drives IgG1 and IgG3 class switch (11, 12). Defective Author contributions: C.-K.W., A.B.A., P.L., and W.J.L. designed research; C.-K.W., A.B.A., R.S., signaling by IL-21 appears to substantially explain the B-cell P.L., M.K., J.O., L.S., P.A.S., E.P.S., and A.F.F. performed research; C.-K.W., A.B.A., R.S., P.L., defect observed in patients with XSCID (11, 13). Furthermore, M.K., D.B.M., and W.J.L. analyzed data; and C.-K.W., A.B.A., P.L., D.B.M., J.D.M., S.M.H., and W.J.L. wrote the paper. IL-21 can enhance the cytotoxic activity of NK and NKT cells (1) Reviewers: T.R.M., Miller School of Medicine, University of Miami; and H.A.Y., National and induce the apoptosis of conventional dendritic cells (14). Cancer Institute. IL-21 activates multiple signaling pathways, including the Conflict of interest statement: W.J.L. and R.S. are inventors on NIH patents related to IL-21. JAK-STAT, PI 3-kinase (PI3K), and MAPK pathways (15). Of Data deposition: The data reported in this paper have been deposited in the Gene Ex- these, the JAK-STAT pathway has been most extensively stud- pression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession no. GSE63204). ied. IL-21 induces phosphorylation of JAK1 and JAK3, which 1C.-K.W., and A.B.A. contributed equally to this work. in turn leads to phosphorylation and nuclear translocation of 2Present address: Department of Nutrition, Harvard T.H. Chan School of Public Health, STAT3, which then binds to IFN-γ–activated sequence (GAS) Boston, MA 02115. – 3 motifs and modulates expression of IL-21 responsive genes. To whom correspondence should be addressed. Email: [email protected]. – IL-21 also activates STAT1, but the function of IL-21 activated This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. STAT1 is largely unknown, although IL-21 was suggested to use 1073/pnas.1511711112/-/DCSupplemental. 9394–9399 | PNAS | July 28, 2015 | vol. 112 | no. 30 www.pnas.org/cgi/doi/10.1073/pnas.1511711112 Downloaded by guest on September 29, 2021 and B). pSTAT1 as well as pSTAT3 was still detected at 4 and 8 h signaling (19). Moreover, we observed augmented IL-21– of stimulation (Fig. 1 A and B), and when we deleted Stat3 by induced expression of a number of genes in the absence of crossing Stat3-floxed mice to CD4-Cre transgenic mice (referred to STAT1 or STAT3, suggesting that these STAT proteins also − − as Stat3 / herein), IL-21 induced more pSTAT1 at 4 and 8 h in directly or indirectly inhibit expression. Notably, nearly ∼50% − − + Stat3 / CD4 T cells than in WT cells (Fig. 1 A and C); this in- (84 of 173) of IL-21–regulated, STAT1-dependent genes were + crease was minimally observed in CD8 Tcells(Fig.1B and C). also STAT3-dependent (Fig. 2C and Dataset S3). Some genes Interestingly, we observed diminished IL-21–induced expression were differentially regulated by STAT1 and STAT3. For exam- − − of Socs3 and Socs1 in Stat3 / cells (Fig. 1D). Because SOCS3 and ple, the Th1 cell signature genes Tbx21 (Fig. 2D) and Ifng (Fig. SOCS1 can negatively regulate cytokine signaling by blocking 2E) were not induced by IL-21 in the absence of STAT1, but STAT protein phosphorylation (20), this might in part explain the their expression was elevated in the absence of STAT3, consis- increased pSTAT1 in the absence of STAT3. Using ImageStream tent with an inducing role for STAT1 and repressive role for + STAT3. This finding is also consistent with a report showing that to image fluorescently labeled pSTAT1 and pSTAT3 within CD4 + IL-21 induces Tbet expression in CD8 T cells via STAT1 (16). T cells, we confirmed that both STAT1 and STAT3 translocated – to the nucleus after IL-21 stimulation (Fig. 1E and Fig. S1). We hypothesized that IL-21 activated STAT1 and STAT3 di- rectly regulated the expression these genes and therefore used + Both STAT1 and STAT3 Contribute to IL-21–Mediated Gene Regulation ChIP-Seq to determine STAT1 and STAT3 binding in CD4 T − − – in CD4+ T Cells. We next used RNA-Seq in WT, Stat1 / , and cells after IL-21 stimulation.
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