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* Department of Pediatrics, University of Washington School of Medicine and Children’s Hospital, Seattle, WA 98109;
Department of Pediatrics, and
Department of Pathology and Laboratory Medicine, The Children’s Hospital of Philadelphia and the University of Pennsylvania School of Medicine, Philadelphia, PA 19104;
Department of Genetics, Albert Einstein College of Medicine of Yeshira University, Bronx, NY 10461;
¶ Oklahoma Medical Research Foundation, Oklahoma City OK 73104; and
|| Department of Pediatrics, University of Alabama, Birmingham, AL 35249
The forkhead DNA-binding protein FOXP3 is critical for the development and suppressive function of CD4+CD25+ regulatory T cells (TREG), which play a key role in maintaining self-tolerance. Functionally, FOXP3 is capable of repressing transcription of cytokine genes regulated by NFAT. Various mechanisms have been proposed by which FOXP3 mediates these effects. Using novel cell lines that inducibly express either wild-type or mutant FOXP3, we have identified NFAT2 as an early target of FOXP3-mediated transcriptional repression. NFAT2 is typically expressed at low levels in resting T cells, but is up-regulated by NFAT1 upon cellular activation. We demonstrate that transcription from the NFAT2 promoter is significantly suppressed by FOXP3, and NFAT2 protein expression is markedly diminished in activated CD4+CD25+FOXP3+ TREG compared with CD4+CD25–FOXP3– T cells. Chromatin immunoprecipitation experiments indicate that FOXP3 competes with NFAT1 for binding to the endogenous NFAT2 promoter. This antagonism of NFAT2 activity by FOXP3 is important for the anergic phenotype of TREG, as ectopic expression of NFAT2 from a retroviral LTR partially restores expression of IL-2 in FOXP3+ TREG. These data suggest that FOXP3 functions not only to suppress the first wave of NFAT-mediated transcriptional responses, but may also affect sustained NFAT-mediated inflammatory gene expression through suppression of inducible NFAT2 transcription.
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 with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grants HD043376–03 (to T.R.T.), HD17427 (to H.D.O.), P20RR016478 (to M.C.), 5U19AI062629 (to M.C.), P20RR15577 (to M.C.), P20RR17703 (to M.C.), R01AI070807 (to A.D.W.), and R01AR48257 (to R.Q.C.). This work was also supported by USIDNet Grant N01-AI30070 (to T.R.T.), the Biesecker Pediatric Liver Center (to A.D.W.), and OCAST Grant HR04–110 (to M.C.).
2 Address correspondence and reprint requests to Dr. Troy R. Torgerson, 1900 9th Avenue, Seattle, WA 98101-1304; E-mail address: troy.torgerson{at}seattlechildren's.org. Dr. Andrew D. Wells, 916 E. Abramson Research Center, 3615 Civic Center Boulevard, Philadelphia, PA 19104; E-mail address: adwells{at}mail.med.upenn.edu. Dr. Randy Q. Cron, 1600 7th Avenue South, CPP 210, Birmingham, AL 35233-1711; E-mail address: rcron{at}peds.uab.edu
3 Abbreviations used in this paper: TREG, regulatory T cell; WT, wild type; ChIP, chromatin immunoprecipitation; MFI, mean fluorescence intensity; NGFR, nerve growth factor receptor.
4 The online version of this article contains supplemental material.
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