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T Cells + IL-4 Expression in CD4 KLF13 Cooperates with C-Maf to Regulate

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T Cells + IL-4 Expression in CD4 KLF13 Cooperates with C-Maf to Regulate KLF13 Cooperates with c-Maf To Regulate IL-4 Expression in CD4 + T Cells Seok Joo Kwon, Juan Crespo-Barreto, Wei Zhang, Tianhong Wang, Dong Seok Kim, Alan Krensky and Carol Clayberger This information is current as of September 26, 2021. J Immunol published online 12 May 2014 http://www.jimmunol.org/content/early/2014/05/10/jimmun ol.1302830 Downloaded from Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision http://www.jimmunol.org/ • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription by guest on September 26, 2021 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 All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published May 12, 2014, doi:10.4049/jimmunol.1302830 The Journal of Immunology KLF13 Cooperates with c-Maf To Regulate IL-4 Expression in CD4+ T Cells Seok Joo Kwon,*,1 Juan Crespo-Barreto,*,1 Wei Zhang,*,1 Tianhong Wang,* Dong Seok Kim,* Alan Krensky,*,†,‡ and Carol Clayberger*,† Kruppel-like factor (KLF) 13 is a transcription factor that positively regulates expression of the chemokine RANTES 3–5 d after activation of T cells. In this study, we document a key role for KLF13 in the expression of IL-4 in CD4+ T cells. Gene expression analysis in activated T cells from Klf132/2 mice showed that IL-4, along with other Th2 cytokine genes, was downregulated when compared with cells from wild-type mice. The decreased levels of IL-4 were not associated with changes in expression of the Th2- inducing transcription factors GATA3 or c-Maf. Additional analysis revealed that KLF13 directly binds to IL-4 promoter regions and synergizes with c-Maf to positively regulate IL-4 expression. These results indicate that KLF13 is a positive regulator for differentiation of Th2 cells, as part of the transcriptional machinery that regulates IL-4 production in Th2 cells. The Journal of Downloaded from Immunology, 2014, 192: 000–000. D4+ T cells mediate a variety of critical roles in adaptive autocrine effect can also regulate Th2 cell differentiation via immune responses. Once triggered by Ag and cytokines, production of other cytokines such as IL-5 and IL-13 (8). C naive CD4+ T cells can differentiate into at least four GATA3 and c-Maf are Th2-specific transcription factors. GATA3 different subsets: Th1, Th2, Th17, and induced T regulatory cells has been called a master regulator for development of Th2 cells http://www.jimmunol.org/ (1). Th1 cells are critical for immune responses against intracel- because it binds to loci of several genes required for Th2 development lular pathogens and produce IFN-g, TNF-a, and IL-2. Th2 cells and function (16–18). c-Maf is a member of the basic-region leucine- are involved in humoral immunity as well as the development of zipper (b-zip) protein and was the first transcription factor identified allergy and other allergic diseases through the production of a variety as a regulator of Th2 cell differentiation (9). Together with IFN of cytokines, including IL-4, IL-5, IL-9, IL-10, IL-13, IL-21, and regulatory factor (IRF) 4 and NFAT, c-Maf promotes IL-4 expression IL-25 (1). Th17 cells can produce IL-17, which has a critical role (19) and positively regulates IL-2R a-chain expression (11, 20) in in autoimmune diseases and inflammation (2), whereas regulatory Th2 cells. Recently, it was reported that c-Maf contains three tyro- T cells suppress the immune response via IL-10 and TGF-b1(3). sines whose phosphorylation is important for IL-4 production (21). IL-4 is a pleiotropic cytokine produced by CD4+ T cells, Kruppel-like factors (KLFs) are a subclass of zinc finger tran- by guest on September 26, 2021 NKT cells, basophils, and mast cells (4). IL-4 functions as an scription factors that play important roles in different aspects of initiator of Th2 cell development, a regulator for MHC class II cell growth, development, and differentiation. KLFs have a DNA expression, an inducer of Ab isotype switching in B cells, and binding domain containing three C2H2-type zinc fingers that bind a modulator of B cell growth (5–7). IL-4 autoregulates its own to either a CACCC element or a GC box in the proximal promoter expression through its receptor and several transcription factors (1, of targeted genes. Our group have identified KLF13 as an essential 8). IL-4 binds to the IL-4R a-chain (IL-4Ra), resulting in the transcription factor for the late expression of chemokine RANTES phosphorylation and activation of STAT6. Phosphorylated STAT6 in T lymphocytes (22). KLF13 also acts as a negative regulator for then translocates into the nucleus and—together with TCR sig- the antiapoptotic protein BCLXL (23) and positively regulates the naling and transcription factors, including GATA3, c-Maf (9–11), expression of Rcn3 (BC025602) and Eomesodermin (Eomes) in and NFAT (8, 12)—regulates IL-4 expression (13–15). This naive CD8+ T cells (24). However, other transcriptional targets of KLF13, as well as its role in T cell lineage determination, have not been fully elucidated. To address this issue, we sought to identify genes that are *Laboratory of Cellular and Molecular Biology, National Cancer Institute, National + Institutes of Health, Bethesda, MD 20892; †Department of Microbiology and Immu- regulated by KLF13 in mouse CD4 T cells. Using microarray + nology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611; analysis, we compared gene expression in activated CD3 T ‡ and Department of Pediatrics, Feinberg School of Medicine, Northwestern Univer- lymphocytes from wild-type (WT) and Klf132/2 animals. Im- sity, Chicago, IL 60611 1 portantly, several Th2 cytokines, including IL-4, were among the S.J.K, J.C.-B., and W.Z. contributed equally to this work. genes found to be misregulated in Klf132/2 CD3+ lymphocytes. Received for publication October 21, 2013. Accepted for publication April 11, 2014. Our studies revealed that KLF13 enhances IL-4 production via at This work was supported by the Intramural Research Program of the National In- least two mechanisms: it binds directly to the IL-4 promoter, and it stitutes of Health, National Cancer Institute, and the Center for Cancer Research. interacts with the Th2-specific transcription factor c-Maf. Thus, The sequences presented in this article have been submitted to Gene Expression Omnibus (www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSM1224728) under ac- KLF13 is a new member of the transcription factor family that cession number GSE50617. regulates the expression of IL-4 in Th2 cells. Address correspondence and reprint requests to Prof. Carol Clayberger, Department of Microbiology and Immunology, Feinberg School of Medicine, Tarry 6-735, Chi- Materials and Methods cago, IL 60611. E-mail address: [email protected] Mice and cell culture conditions Abbreviations used in this article: ChIP, chromatin immunoprecipitation; IL-4Ra, 2/2 IL-4R a-chain; IRF, IFN regulatory factor; KLF, Kruppel-like factor; m, murine; Klf13 mice on a BALB/c background were generated and maintained MARE, Maf recognition element; siRNA, small interfering RNA; WT, wild-type. as previously described (24). All animal studies were reviewed and www.jimmunol.org/cgi/doi/10.4049/jimmunol.1302830 2 KLF13 REGULATES IL-4 EXPRESSION approved by the Animal Care Committee of the National Cancer Institute. ATATAGAGTTAAAGTTGAGTCAACCAAGGGAAAATG-39); IL-4 pro- EL4 cells were cultured in RPMI 1640 supplemented with 10% FBS and moter luciferase 0.23 kb MU2 (forward: 59-CTCCTGGAAGAGAGGAT- 100 U/ml penicillin/streptomycin at 37˚C in 95% humidity and 5% CO2. TAGATTGGCCCAGAATAAC-39, reverse: 59-GTTATTCTGGGCCAAT- Primary murine T cells were cultured in RPMI 1640 supplemented with CTAATCCTCTCTTCCAGGAG-39); and IL-4 promoter luciferase 0.23 kb 10% FBS, 100 U/ml penicillin/streptomycin, and 55 mM 2-mercapto- MU3 (forward: 59-CATTTTCCCTTGGTTGACTCAACTTTAACTCTAT- ethanol at 37˚C in 95% humidity and 5% CO2. AT-39, reverse: 59-ATATAGAGTTAAAGTTGAGTCAACCAAGGGAAA- ATG-39). cDNA microarrays and quantitative RT-PCR Transfection and luciferase assay CD3+ T cells were isolated using the EasySep Negative Selection Mouse T Cell Enrichment Kit (STEMCELL Technologies, Vancouver, Canada) For transfection, 4 3 106 EL4 cells were transiently transfected with 5 mg from spleens of five WT or Klf132/2 mice. Isolated cells (3–5 3 106/ml) plasmid DNA using the Amaxa Cell Line Nucleofactor Kit V (Lonza, were cultured for 4 d on tissue culture plates precoated with 3 mg/ml anti- Walkersville, MD) and pRL-SV40 Renilla luciferase was used as a control mouse CD3 Ab (BioLegend, San Diego, CA) and 3 mg/ml soluble anti- vector (Promega). After transfection, cells were cultured with 10 ng/ml PMA mouse CD28 Ab (BioLegend). On day 4, cells were harvested and total and 1 mM ionomycin for 14 h, and luciferase activity was analyzed with the RNA was isolated using the RNeasy Kit (QIAGEN, Valencia, CA). Dual-Luciferase Reporter Assay System (Promega). Data were normalized Microarray analysis was performed at the Laboratory of Molecular using Renilla levels from cotransfected pRL-SV40 control vector. Technology at the Frederick National Laboratory for Cancer Research (Frederick, MD), using Affymetrix GeneChip Mouse Gene St 1.0 ST. Intracellular staining and flow cytometry Microarray data were analyzed using Partek Genomics Suite software All Abs for FACS were purchased from BD Biosciences (San Jose, CA) and , .
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