Foxp3 interacts with c-Rel to mediate NF-κB repression.

Expression of the lineage-specific DNA-binding factor Foxp3 controls the development and function of naturally occurring regulatory T cells. Foxp3 has been shown to interact with a multitude of transcriptional regulators including NFAT, NF-κB (p65), Runx1 and RORγt, as well as the histone modification enzymes TIP60, HDAC7 and HDAC9. The sum of these interactions is believed to cause the change in the transcriptional program of regulatory T cells. Here we show that Foxp3 directly or as part of a multimeric complex engages with the NF-κB component c-Rel. We demonstrate that the N-terminal region of Foxp3 is required for the binding of c-Rel, but not NFAT. Conversely, deletion of the forkhead domain causes a loss of interaction with NFAT, but not c-Rel. Our findings are of particular interest, as c-Rel is crucial for the induction of Foxp3 in regulatory T cells during thymic development, but has to be repressed in mature regulatory T cells to maintain their suppressive phenotype.