A mechanism involving sibling transcription factor assistance preserves the integrity of an active Foxp3 locus in peripherally induced regulatory T cells.

Abstract

Abstract Regulatory T (Treg) cell mediated dominant negative regulation is critical for suppressing hyper-immune responses. Broadly classified as thymus derived (tTreg) and peripherally induced (iTreg), these cells share a stringent dependence on the transcription factor Foxp3. In spite of significant advances, precise understanding of the molecular events that promote and preserve unceasing expression of Foxp3 in Treg cells is still incompletely understood. Here we show that Foxp1, a forkhead transcription factor and thus a sibling family member of Foxp3, is essential for sustained high level expression of Foxp3 specifically in iTreg cells. By being readily associated with the Foxp3 locus in a TGFβ dependent manner, Foxp1 critically participates during multiple phases of iTreg development and maturity. By employing an inducible model of temporal deletion of Foxp1 in precursor CD4+ T cells, we found that it is required for optimum expression of Foxp3 during the onset of iTreg induction. Even a conditional ablation of Foxp1 in iTreg cells at a later developmental time point, when high level transcription of Foxp3 was already established, resulted in dramatic instability of the differentiated cell state. Accordingly, Treg specific deletion of Foxp1 renders cells gradually lose Foxp3, resulting in dramatically reduced Nrp1−Helios− iTreg compartment in mice, ensuing significantly augmented intestinal inflammation. Interestingly, the stability of Foxp3 expression in tTreg cells remained unaffected in the absence of Foxp1. Thus, our study unravels a mechanistic module of evolutionarily akin members of a transcription factor subfamily in establishing a novel molecular program indispensable to ensure efficient immune homeostasis.