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Promoter Through Interaction with the FOXP3 RORC2 Is Involved in T Cell Polarization

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Promoter Through Interaction with the FOXP3 RORC2 Is Involved in T Cell Polarization RORC2 Is Involved in T Cell Polarization through Interaction with the FOXP3 Promoter This information is current as Simone Burgler, Pierre-Yves Mantel, Claudio Bassin, Nadia of September 28, 2021. Ouaked, Cezmi A. Akdis and Carsten B. Schmidt-Weber J Immunol 2010; 184:6161-6169; Prepublished online 28 April 2010; doi: 10.4049/jimmunol.0903243 http://www.jimmunol.org/content/184/11/6161 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2010/04/28/jimmunol.090324 Material 3.DC1 http://www.jimmunol.org/ References This article cites 64 articles, 27 of which you can access for free at: http://www.jimmunol.org/content/184/11/6161.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 28, 2021 • 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 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 © 2010 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology RORC2 Is Involved in T Cell Polarization through Interaction with the FOXP3 Promoter Simone Burgler,* Pierre-Yves Mantel,*,† Claudio Bassin,* Nadia Ouaked,* Cezmi A. Akdis,* and Carsten B. Schmidt-Weber‡ The process of Th cell differentiation toward polarized effector T cells tailors specific immunity against invading pathogens while allowing tolerance against commensal microorganisms, harmless allergens, or autologous Ags. Identification of the mechanisms underlying this polarization process is therefore central to understand how the immune system confers immunity and tolerance. The present study demonstrates that retinoic acid receptor-related orphan receptor C2 (RORC2), a key transcription factor in Th17 cell development, inhibits FOXP3 expression in human T cells. Although overexpression of RORC2 in naive T cells reduces levels of FOXP3, small interfering RNA-mediated knockdown of RORC2 enhances its expression. RORC2 mediates this inhibition at least partially by binding to two out of four ROR-responsive elements on the FOXP3 promoter. Knockdown of RORC2 promotes high Downloaded from FOXP3 levels and decreased expression of proinflammatory cytokines b form of pro-IL-1, IL-6, IL-17A, IFN-g, and TNF-a in differentiating naive T cells, suggesting that the role of RORC2 in Th17 cell development involves not only induction of Th17- characteristic genes, but also suppression of regulatory T cell-specific programs. Together, this study identifies RORC2 as a polarizing factor in transcriptional cross-regulation and provides novel viewpoints on the control of immune tolerance versus effector immune responses. The Journal of Immunology, 2010, 184: 6161–6169. http://www.jimmunol.org/ D4+ effector cells can be divided into different subsets neutrophil-attracting chemokines in epithelial or other tissue cells according to their phenotype and function. Each subset is (2). In contrast to the effector subsets, regulatory T cells (Tregs) C crucial for mounting an appropriate immune response to restrict the strength and duration of the response and establish a certain type of pathogen (1, 2). Differentiation of naive Th cells tolerance to harmless self- and non–self-Ags. Failure in either toward a specific effector subset is therefore an important process development or function of Tregs causes severe hyperproliferative in immune system homeostasis. T cell development is governed diseases and is assumed to underlie autoimmune and allergic by lineage-specific transcription factors that regulate expression of disorders. FOXP3 is the master regulator of Tregs. Retroviral gene characteristic surface receptors and cytokines. The Th1-specific transfer of FOXP3 is sufficient to convert naive T cells into a Treg by guest on September 28, 2021 T box transcription factor (T-bet), for example, coordinates pro- phenotype (6) and confers suppressor function on peripheral CD4+ duction of IFN-g and TNF-a (3), whereas the GATA-binding CD252 T cells (7, 8). Expression of FOXP3 is regulated through protein 3 (GATA-3) regulates Th2 development including pro- interaction of several TCR-induced transcription factors, including duction of their characteristic cytokines IL-4, IL-5, IL-9, and NFAT, AP-1, and cAMP response element binding protein IL-13 (4). Development of Th17 cells and expression of their (CREB)/activating transcription factor, with the promoter or an specific cytokines IL-17A, IL-17F, and IL-26 is promoted by the enhancer element of the foxp3 gene (9–12). Although TCR retinoic acid receptor-related orphan receptor gt/C2 (RORgt/ stimulation induces basal levels of FOXP3, maximal and sustained RORC2) (5). Along with Th1 and Th2 cells, Th17 cells promote FOXP3 expression requires additional stimulation by cytokines inflammatory reactions and are important for the induction of such as IL-2, TGF-b, and IL-27 (10, 13–16). Cross-inhibition of T cell subsets during differentiation is an important mechanism to ensure expansion of the polarized pop- *Swiss Institute of Allergy and Asthma Research, Davos, Switzerland; †Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA ulations. Cytokines produced by one subset inhibit differentiation of 02115; and ‡Centre of Allergy and Environment, Technical University and Helmholtz other subsets. This antagonism is mirrored on the level of tran- Centre Munich, Munich, Germany scription factors, which cross-regulate each other and finally imprint Received for publication October 6, 2009. Accepted for publication March 26, 2010. or unlock the transcriptional program on the chromatin. T-bet di- This work was supported by the Swiss National Science Foundation Grants 310000- rectly inhibits Th2 differentiation by binding to its master regulator 112329 and 3200B0-118226. GATA-3, preventing it from DNA binding and activation of Th2- Address correspondence and reprint requests to Prof. Dr. Carsten Schmidt-Weber, specific genes (17, 18). Likewise, GATA-3 can downregulate Director of the Centre of Allergy and Environment, Technical University and Helm- holtz Centre Munich, Biedersteiner Strasse 29, 80802 Munich, Germany. E-mail STAT4, a transcription factor important for Th1 differentiation address: [email protected] (19). By binding to GATA-binding sites in the FOXP3 promoter, The online version of this article contains supplemental material. GATA-3 also negatively regulates FOXP3 expression and thereby Abbreviations used in this paper: ChIP, chromatin immunoprecipitation; DBD, DNA- inhibits Treg differentiation (20). The Th17-driving transcription binding domain; GATA-3, GATA-binding protein 3; IL-1b, b form of pro-IL-1; MFI, factor RORC2 is expressed by both Treg and Th17 cells, whereas median fluorescence intensity; mut, mutated; ROR, retinoic acid receptor-related orphan receptor; RORE, retinoic acid receptor-related orphan receptor response ele- only Tregs express FOXP3 (21–23). In Tregs, FOXP3 suppresses ment; siRNA, small interfering RNA; siScram, scrambled siRNA; T-bet, Th1-specific transcriptional activity of RORC2 by direct interaction, thereby T box transcription factor; Treg, regulatory T cell; TSS, transcription start site; wt, inhibiting Th17 differentiation (22, 24). wild-type. RORC2 belongs to the family of RORs that consists of three Copyright Ó 2010 by The American Association of Immunologists, Inc. 0022-1767/10/$16.00 members: RORA (NR1F1, RORa, RZRa), RORB (NF1F2, RORb, www.jimmunol.org/cgi/doi/10.4049/jimmunol.0903243 6162 RORC2 INHIBITS Tregs THROUGH INTERACTION WITH FOXP3 PROMOTER RZRb), and RORC (NF1F3, RORg, RZRg). All ROR genes gen- to remove the cytokines used for differentiation. Supernatants were col- erate several isoforms, which differ only in their N termini (25–27). lected 48 h after restimulation, and concentrations of IL-1b, IL-2, IL-5, IL- Proteins of the ROR family display a typical nuclear receptor do- 6, IL-13, IL-17A, IFN-g, and TNF-a were determined by cytometric bead array (Bio-Rad) according to the manufacturer’s protocol. main structure consisting of four domains: an N-terminal domain, a highly conserved DNA-binding domain (DBD), a hinge domain, Western blotting and a C-terminal ligand-binding domain. The DBD binds to DNA, Protein extraction was performed as follows: the cells were pelleted and containing a so-called ROR response element (RORE), which resuspended in buffer C (20 mM HEPES [pH 7.9], 420 mM NaCl, 1.5 mM consists of the DNA sequence GGTCA as a core motive, preceded MgCl2, 0.2 mM EDTA, 1 mM DTT, protease inhibitors [Roche Diagnostic by an A/T-rich sequence (28, 29). In contrast to other nuclear re- Systems, Somerville, NJ], and 0.1% Nonidet P-40) and incubated at 4˚C with ceptors, ROR family proteins bind DNA as monomers (26, 28, 30). agitation for 15 min. Insoluble material was removed by centrifugation, and the supernatants were diluted one-third with buffer D (as buffer C, but without They can interact with both coactivators and corepressors to posi- NaCl). Total
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