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1598.Full.Pdf IFN Regulatory Factor 4 Regulates the Expression of a Subset of Th2 Cytokines Ayele-Nati N. Ahyi, Hua-Chen Chang, Alexander L. Dent, Stephen L. Nutt and Mark H. Kaplan This information is current as of October 1, 2021. J Immunol 2009; 183:1598-1606; Prepublished online 10 July 2009; doi: 10.4049/jimmunol.0803302 http://www.jimmunol.org/content/183/3/1598 Downloaded from References This article cites 45 articles, 28 of which you can access for free at: http://www.jimmunol.org/content/183/3/1598.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 *average by guest on October 1, 2021 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 © 2009 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology IFN Regulatory Factor 4 Regulates the Expression of a Subset of Th2 Cytokines1 Ayele-Nati N. Ahyi,*† Hua-Chen Chang,* Alexander L. Dent,† Stephen L. Nutt,‡ and Mark H. Kaplan2*† Th2 cells can be subdivided into subpopulations depending on the level of a cytokine and the subsets of cytokines they produce. We have recently identified the ETS family transcription factor PU.1 as regulating heterogeneity in Th2 popula- tions. To define additional factors that might contribute to Th2 heterogeneity, we examined the PU.1 interacting protein IFN-regulatory factor (IRF)4. When Th2 cells are separated based on levels of IL-10 secretion, IRF4 expression segregates into the subset of Th2 cells expressing high levels of IL-10. Infection of total Th2 cells, and IL-10 nonsecreting cells, with retrovirus-expressing IRF4, resulted in increased IL-4 and IL-10 expression, no change in IL-5 or IL-13 production and decreased Il9 transcription. Transfection of an IRF4-specific small interfering RNA into Th2 cells decreases IL-10 produc- Downloaded from tion. IRF4 directly binds the Il10 gene as evidenced by chromatin immunoprecipitation assay, and regulates Il10 control elements in a reporter assay. IRF4 interacts with PU.1, and in PU.1-deficient T cells there was an increase in IRF4 binding to the Il10 gene, and in the ability of IRF4 to induce IL-10 production compared with wild-type cells and Il10 promoter activity in a reporter assay. Further heterogeneity of IRF4 expression was observed in Th2 cells analyzed for expression of multiple Th2 cytokines. Thus, IRF4 promotes the expression of a subset of Th2 cytokines and contributes to Th2 heterogeneity. The Journal of Immunology, 2009, 183: 1598–1606. http://www.jimmunol.org/ D4ϩ Th cells play a critical role in modulating both in- IFN-regulatory factor (IRF)3-4 was first identified as a protein nate and adaptive immune responses. Cytokines direct recruited by the transcription factor PU.1 to an Ig ␬ 3Ј enhancer in C the differentiation of precursor CD4ϩ Th cells into com- a cooperative manner (9–12) and contributes to the differentiation mitted Th phenotypes, Th1, Th17, and Th2 cells, which are defined of Th2, Th17, and some functions of Treg cells (13–15). IRF4 also by their function and the array of secreted cytokines (1–3). Th2 has distinct effects on cytokine production in naive vs memory T cells mediate humoral immune responses by secreting IL-4, IL-5, cell populations (16). In Th2 cells, IRF4 binds to a site adjacent to IL-9, IL-13, and other cytokines including the anti-inflammatory a NFAT binding element and cooperates with NFATc1, NFATc2, cytokine IL-10. The differentiation of Th2 cells in vivo upon in- and c-maf in the transcription of IL-4 (17, 18). These interactions by guest on October 1, 2021 fection or in vitro generates a heterogenous population of Th2 cells are likely important as the activation of T cells triggers a rapid that express and secrete various combinations of Th2-type cyto- induction of IRF4 (19, 20) and IRF4-deficient T cells secrete de- kines at different levels (4–6). Although Th2 heterogeneity is well creased levels of Th2 cytokines (13). Ectopic IRF4 has been shown documented, the origins are still unclear. Guo et al. (7) reported to increase the level of IL-10 secreted by Jurkat cells, but the that the Il4 gene in IL-4-producing and nonproducing cells has mechanism by which IRF4 controls the expression of Th2-cyto- differential levels of CpG methylation and histone acetylation. kines in differentiated Th2 cells has not been examined. In this These modifications translate in an open DNA conformation and report, we determine that IRF4 is a regulator of a subset of Th2 gene activation in IL-4-producing cells. We reported that PU.1 cytokines, and contributes to Th2 heterogeneity. plays a critical role in establishing these phenotypes by preventing GATA-3 binding to the IL-4 locus resulting in an IL-4 low Th2 Materials and Methods population (8). Knock-down of PU.1 expression resulted in in- Mice creased homogeneity of Th2 cells (8). In addition to PU.1, it is Wild-type (WT) C57BL/6 and BALB/c mice (Harlan Bioscience) were likely that additional factors are involved in the establishment of used for Th1 and Th2 differentiation. Conditional mutant Sfpi1 mice on the Th2 subpopulations. C57BL/6 background were previously described (21) and were mated to lck-Cre expressing mice (noted as Sfpi1lckϪ/Ϫ). Mice were maintained in pathogen-free conditions and all studies were approved by the Indiana University School of Medicine Animal Care and Use Committee. *Department of Pediatrics, Herman B. Wells Center for Pediatric Research, †Depart- ment of Microbiology and Immunology, and the Walther Cancer Institute, Indiana University School of Medicine, Indianapolis, IN 46202; and ‡The Walter and Eliza Th1 and Th2 cell differentiation Hall Institute of Medical Research, Victoria, Australia CD4ϩ T cells were purified from spleen and lymph nodes by positive Received for publication October 2, 2008. Accepted for publication May 31, 2009. selection using magnetic beads (Miltenyi Biotec) with purity Ͼ97% by ␮ The costs of publication of this article were defrayed in part by the payment of page FACS analysis. Cells were activated with 2 g/ml plate-bound anti-CD3 charges. This article must therefore be hereby marked advertisement in accordance (145–2C11) plus 1 ␮g/ml anti-CD28, in addition to 10 ng/ml IL-4 and 10 with 18 U.S.C. Section 1734 solely to indicate this fact. 1 This work was supported by U.S. Public Health Service Award AI057459 (to 3 Abbreviations used in this paper: IRF, IFN-regulatory factor; WT, wild type; ChIP, M.H.K.) from the National Institutes of Health. chromatin immunoprecipitation assay; siRNA, small interfering RNA; qPCR, quan- 2 Address correspondence and reprint requests to Dr. Mark H. Kaplan, Department of titative PCR; DAPA, DNA affinity purification assay; GATA-3, GATA binding Pediatrics, and Microbiology and Immunology, Wells Center for Pediatric Research, protein-3. Indiana University School of Medicine, 702 Barnhill Drive, RI 2600, Indianapolis, IN 46202. E-mail address: [email protected] Copyright © 2009 by The American Association of Immunologists, Inc. 0022-1767/09/$2.00 www.jimmunol.org/cgi/doi/10.4049/jimmunol.0803302 The Journal of Immunology 1599 ␮g/ml anti-IFN-␥ (R4/6A2 or XMG) for Th2 differentiation, or 10 ng/ml were labeled using the mouse IL-10 Secretion Assay (Miltenyi Biotec) IL-12 plus 10 ␮g/ml anti-IL-4 (11B11) for Th1 differentiation. After 3 days before sorting with FACSVantage SE or FACSAria from Becton Dick- of incubation, cells were expanded for a total of 5 or 6 days. Differentiated inson. The cells were rested for 1 or 2 days before restimulation, anal- cells were restimulated with 2 ␮g/ml anti-CD3 at a concentration of 106 ysis, or transduction. cells/ml for real-time PCR and ELISA as previously described (8, 22). Statistics were performed using a t test with SPSS software (v. 16.0; SPSS). IL-10 high and low Th2 cocultures ϫ 6 Immunoprecipitation and Western blot analysis IL-10 high and low Th2 (1 10 ) cells were sorted as described above and cocultured with either 0.5 ϫ 106 splenic CD11cϩ cells purified by positive Total cell extracts were prepared by lysing Th2 cells with lysis buffer (10% selection using magnetic beads (Miltenyi Biotech) or 1 ϫ 106 total spleno- glycerol,1% Igepal, 50 mM Tris (pH 7.4), 150 mM NaCl, 1 mM EDTA cytes from BALB/c mice. Cells supplemented with RPMI 1640 medium (pH 8)) for 15 min on ice before centrifugation at 14,000 rpm for 15 min were activated with 5 ␮g/ml anti-CD3 and 4 ␮g/ml LPS. dendritic cell at 4°C. Nuclear and cytoplasmic proteins were prepared from differentiated coculture was harvested after 3 days for IFN-␥ and IL-6 ELISA and total Th2 cells using Nuclear and Cytoplasmic Extraction Reagents from Pierce splenocyte coculture was harvested after 5 days for IgG1 ELISA. Biotechnology. Protein extracts (25 ␮g) from naive T, Th1, Th2, and Phoe- nix cells were separated on 4–12% SDS-PAGE and transferred onto Ny- Chromatin immunoprecipitation assay (ChIP) tran membranes (Schleicher and Schuell Bioscience).
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