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IL-17-Secreting Th Cells Stat3 and Stat4 Direct Development Of Stat3 and Stat4 Direct Development of IL-17-Secreting Th Cells Anubhav N. Mathur, Hua-Chen Chang, Dimitrios G. Zisoulis, Gretta L. Stritesky, Qing Yu, John T. O'Malley, This information is current as Reuben Kapur, David E. Levy, Geoffrey S. Kansas and Mark of September 29, 2021. H. Kaplan J Immunol 2007; 178:4901-4907; ; doi: 10.4049/jimmunol.178.8.4901 http://www.jimmunol.org/content/178/8/4901 Downloaded from References This article cites 38 articles, 15 of which you can access for free at: http://www.jimmunol.org/content/178/8/4901.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 29, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2007 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Stat3 and Stat4 Direct Development of IL-17-Secreting Th Cells1 Anubhav N. Mathur,2*† Hua-Chen Chang,2*† Dimitrios G. Zisoulis,‡ Gretta L. Stritesky,*† Qing Yu,*† John T. O’Malley,*† Reuben Kapur,* David E. Levy,§ Geoffrey S. Kansas,‡ and Mark H. Kaplan3*† IL-17-secreting CD4؉ T cells are critically involved in inflammatory immune responses. Development of these cells is promoted in vivo and in vitro by IL-23 or TGF␤1 plus IL-6. Despite growing interest in this inflammatory Th subset, little is known about the transcription factors that are required for their development. We demonstrate that Stat3 is required for programming the TGF␤1 plus IL-6 and IL-23-stimulated IL-17-secreting phenotype, as well as for ROR␥t expression in TGF␤1 plus IL-6-primed cells. Moreover, retroviral transduction of a constitutively active Stat3 into differentiating T cell cultures enhances IL-17 pro- duction from these cells. We further show that Stat4 is partially required for the development of IL-23-, but not TGF␤1 plus Downloaded from IL-6-primed IL-17-secreting cells, and is absolutely required for IL-17 production in response to IL-23 plus IL-18. The require- ments for Stat3 and Stat4 in the development of these IL-17-secreting subsets reveal additional mechanisms in Th cell fate decisions during the generation of proinflammatory cell types. The Journal of Immunology, 2007, 178: 4901–4907. nterleukin-17-secreting T cells play critical roles in autoim- the IL-23-primed IL-17-secreting phenotype is not stable after mune disease, immunity to infection, and the homeostatic continued in vitro culture and that following Ag receptor-induced http://www.jimmunol.org/ I regulation of inflammatory cells (1–4). The development of T-bet expression, IL-23-primed cells convert to an IFN-␥-secreting ␥ these cells, which have been variously called Th17, ThIL-17, Tn, phenotype (7). Recently, the transcription factor ROR t was and Th1␤, is only beginning to be understood (5–8). A proinflam- shown to be important in the development of IL-17-secreting T matory cytokine environment containing TGF␤1 plus IL-6 has cells (19). However, cytokine-stimulated transcription factors that been implicated in the generation of IL-17-secreting T cells from promote the IL-17-secreting genetic phenotype have not been naive CD4 T cells (9–11). IL-23, which shares cytokine and re- identified. In this report, we define requirements for Stat3 and ceptor subunits with IL-12 (12, 13), also promotes the develop- Stat4 in the development of IL-17-secreting Th cells. ment of proinflammatory IL-17-secreting cells in vivo and in vitro by guest on September 29, 2021 from Th cells with a memory phenotype (3, 5, 6, 14). Conse- quently, IL-6- and IL-23p19-deficient mice are protected from in- Materials and Methods flammatory autoimmune disease (6, 10, 15). The development of Mice the IL-17-secreting Th subset is negatively regulated by IL-4, IL- All animal studies in this report were approved by the Indiana University Ϫ Ϫ 27, and IFNs (3, 5, 16, 17). Institutional Animal Care and Use Committee. The generation of Stat4 / fl/fl CD4Ϫ/Ϫ Despite the activation of Stat proteins by IL-6 and IL-23 (12, 13, mice and Stat3 mice with a CD4-Cre (Stat3 ) transgene were pre- viously described (20–23). Wild-type (WT;4 Harlan Sprague Dawley) and 18), the development of IL-17-secreting cells was reported to be Stat4Ϫ/Ϫ mice were used on a C57BL/6 background. Stat3fl/fl mice are on independent of Stat4 and Stat6, factors required for the normal a mixed 129-C57BL/6 genetic background and the presence of the CD4- development of Th1 and Th2 cells, respectively (3, 5). In contrast, Cre transgene deletes exons 16–21 in T cells (22). WT mice in experiments CD4Ϫ/Ϫ T-bet, which promotes the development of Th1 cells, is a critical using Stat3 mice were Cre-negative littermates. negative regulator of IL-17-secreting cells. We have shown that Analysis of Th cell differentiation ϩ Ϫ/Ϫ † Naive, memory, or total CD4 T cells were isolated from WT and Stat4 *Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Depart- CD4Ϫ/Ϫ ment of Microbiology and Immunology, and Walther Cancer Institute, Indiana Uni- C57BL/6 or Stat3 and WT littermate spleen and lymph nodes versity School of Medicine, Indianapolis, IN 46202; ‡Department of Microbiology- (MACS isolation system; Miltenyi Biotec) as indicated. T cells were ac- Immunology, Northwestern University Medical School, Chicago, IL 60611; and tivated with plate-bound anti-CD3 (2 ␮g/ml 145-2C11) and soluble anti- §Department of Pathology and Microbiology, New York University School of Med- CD28 (0.5 ␮g/ml; BD Pharmingen). Th1, IL-23-primed, and TGF␤1 plus icine, New York, NY 10016 IL-6-primed cultures were generated with anti-IL-4 (10 ␮g/ml 11B11) and ␤ Received for publication September 15, 2006. Accepted for publication February IL-12 (2 ng/ml; PeproTech), IL-23 (4 ng/ml; R&D Systems), or TGF 1(1 5, 2007. ng/ml; PeproTech) and IL-6 (100 ng/ml; PeproTech) (9), respectively. Af- ter 5 days in culture, 1 ϫ 106 live cells/ml were restimulated with medium The costs of publication of this article were defrayed in part by the payment of page ␮ charges. This article must therefore be hereby marked advertisement in accordance alone, plate-bound anti-CD3 (2 g/ml), or cytokines indicated for 18–24 h with 18 U.S.C. Section 1734 solely to indicate this fact. as described previously (7). Cell-free supernatants were analyzed for IL-17 ␥ 1 and IFN- using ELISA (reagents from BD Pharmingen or R&D Systems). This work was supported by National Institutes of Health Grants AI45515 (to RNA was isolated from Th cultures and message levels of the genes in- M.H.K.) and AI50837 (to G.S.K.). A.N.M. and D.G.Z. are Predoctoral Fellows of the American Heart Association. dicated were analyzed by real-time PCR as described elsewhere (7). RNA 2 A.N.M. and H.-C.C. contributed equally to this work. 3 Address correspondence and reprint requests to Dr. Mark H. Kaplan, Department of Pediatrics, Indiana University School of Medicine, HB Wells Center for Pediatric 4 Abbreviation used in this paper: WT, wild type. Research, 702 Barnhill Drive RI2600, Indianapolis, IN 46202. E-mail address: [email protected] Copyright © 2007 by The American Association of Immunologists, Inc. 0022-1767/07/$2.00 www.jimmunol.org 4902 DEVELOPMENT OF IL-17-SECRETING Th CELLS was isolated from cells stimulated for 0, 4, or 18 h with anti-CD3 as spec- ified in the figure legends. All reagents were obtained from Applied Bio- systems, and real-time PCR was performed according to standard manu- facturers’ protocols. Results are relative to the condition as indicated in the figure legend. Chromatin immunoprecipitation analysis was performed as described (24) using PCR primers that span the IL-17A promoter. Flow cytometry Five-day differentiated Th1 and IL-23-primed cells from Stat3CD4Ϫ/Ϫ and WT littermate controls were analyzed for CXCR3-PE (R&D Systems) by flow cytometry. P- and E-selectin ligand expression was assessed from developing Th1, IL-23-primed, or unskewed (activated CD4ϩ T cells cul- tured with anti-IL-4 alone) cultures as described previously (25, 26). Retroviral transduction Mouse stem cell virus long-terminal repeat and Stat3C retroviruses were prepared by transient transfection of Phoenix-GP packaging cells using a calcium phosphate precipitation method (7). Two million CD4ϩ T cells were differentiated under conditions described previously in the presence of human IL-2 (50 U/ml). Two days after differentiation, cells were trans- duced with Mouse stem cell virus long-terminal repeat or Stat3C retrovirus containing supernatants by centrifugation for1hat2000 rpm at room Downloaded from temperature. The supernatants were removed after the spin infection and replaced with medium containing cytokines and Abs for continued differ- entiation. One day later, cells were expanded with fresh medium in the presence of human IL-2 (25 U/ml). After 6 days of differentiation, cells expressing the truncated mouse MHC class I molecule H-2Kk were posi- tively selected using MACSelect Kk MicroBeads (Miltenyi Biotec).
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