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Inhibition of NFAT2 expression by FOXP3
Author(s) -
Cron Randy Q.,
Wells Andrew D.,
Torgerson Troy R.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.848.27
Subject(s) - nfat , foxp3 , transcription factor , effector , chromatin immunoprecipitation , biology , microbiology and biotechnology , il 2 receptor , t cell , gene expression , promoter , immunology , gene , immune system , genetics
FOXP3 is critical for the development and suppressive function of CD4+CD25+ regulatory T cells (TREG). FOXP3 represses transcription of cytokine genes regulated by the Nuclear Factor of Activated T cells (NFAT). Various mechanisms have been proposed by which FOXP3 mediates these effects. We identified novel FOXP3 regulated genes by microarray analysis using inducible cell lines, and confirmed that WT FOXP3 inhibits NFAT2 expression and transcription of the inducible NFAT2 promoter in primary CD4 T cells by real‐time RT‐PCR and reporter gene analysis, respectively. Moreover, NFAT2 protein expression is markedly diminished in activated CD4+CD25+FOXP3+ TREG compared to CD4+CD25negFOXP3neg T cells. Chromatin immunoprecipitation shows that FOXP3 binds to the NFAT2 promoter and significantly decreases the inducible binding of NFAT1 to the NFAT2 promoter. Overexpression of NFAT2 by retroviral transduction restores expression of IL‐2 in FOXP3‐expressing T cells. 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 responses and effector T cell development through suppression of inducible NFAT2 transcription. Thus, FOXP3 works to inhibit effector cell function via inhibition of NFAT2, a master regulator of cytokine function and effector cell lineage commitment.