Transcription factor Foxp3 and its protein partners form a complex regulatory network

The transcription factor Foxp3 is indispensible for the differentiation and function of regulatory T cells (T(reg) cells). To gain insights into the molecular mechanisms of Foxp-mediated gene expression we purified Foxp3 complexes and explored their composition. Biochemical and mass-spectrometric analyses revealed that Foxp3 forms multi-protein complexes of 400–800 kDa or larger and identified 361 associated proteins, ~30% of which are transcription-related. Foxp3 directly regulated expression of a large proportion of the genes encoding its co-factors. Reciprocally, some transcription factor partners of Foxp3 facilitated its expression. Functional analysis of Foxp3 cooperation with one such partner, GATA-3, provided further evidence for a network of transcriptional regulation afforded by Foxp3 and its associates to control distinct aspects of T(reg) cell biology.