Journal
IMMUNITY
Volume 39, Issue 6, Pages 1057-1069Publisher
CELL PRESS
DOI: 10.1016/j.immuni.2013.11.005
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Funding
- Department of Biotechnology
- Council for Scientific and Industrial Research, Government of India
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FoxP3, a lineage-specification factor, executes its multiple activities mostly through transcriptional regulation of target genes. We identified an interleukin-10 (IL-10)-producing FoxP3(+) T regulatory cell population that contributes to IL-10-dependent type 2 cytokine bias in breast-cancer patients. Although genetic ablation of FOXP3 inhibited IL10 transcription, genome-wide analysis ruled out its role as a transcription factor for IL10. In-depth analysis revealed that histone acetyl transterase-1, in association with FoxP3, modified the IL10 promoter epigenetically, making a space for docking STAT3-FoxP3 complexes. A predictive docking module with target-receptor specificity, along with exon-deletion and site-directed mutagenesis studies, showed that STAT3 binds through its N-terminal floppy domain to the exon 2 beta sheet region of FoxP3 to form STAT3-FoxP3 complexes. Such cotranscriptional activity of FoxP3 extended to other STAT3-target genes that lack FoxP3-binding sites. These results suggest a function of FoxP3, where, failing to achieve direct promoter occupancy, FoxP3 promotes transcription in association with the locus-specific transcription factor STAT3.
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