The Regulatory T Cell Lineage Factor Foxp3 Regulates Gene Expression through Several Distinct Mechanisms Mostly Independent of Direct DNA Binding

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The suppressive activity of regulatory T cells provides the immune system with a mechanism to prevent detrimental immune responses, such as autoimmunity, attack of the beneficial commensal microbiota and rejection of the fetus. Intriguingly, expression of a single lineage factor Foxp3 is sufficient to completely reprogram T cells from a pro-inflammatory to a suppressive phenotype. Here, we show that Foxp3 alters the expression of thousands of genes through several independent mechanisms. In many cases, its own ability to bind to DNA appears to be dispensable, but rather it binds indirectly to the DNA by interaction with other transcription factors. Foxp3 then in turn recruits other proteins that affect gene expression through chromatin modification. For example, Foxp3 indirectly binds to the IL-2 promoter via interaction with the transcriptional activators c-Rel, AML-1 and NFAT. This leads to the Foxp3 mediated recruitment of class I histone deacetylases HDAC1, 2 and 3, which in turn counteracts the activation-induced hyper-acetylation of the promoter, thereby switching the gene off. In a way, Foxp3 hijacks pre-existing regulatory mechanism to reverse the transcriptional expression status of the target gene. By dissecting Foxp3 on a molecular level, we also show that this is only one of several independent mechanism utilised by Foxp3.

Vyšlo v časopise: The Regulatory T Cell Lineage Factor Foxp3 Regulates Gene Expression through Several Distinct Mechanisms Mostly Independent of Direct DNA Binding. PLoS Genet 11(6): e32767. doi:10.1371/journal.pgen.1005251
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1005251

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