Regulatory T (Treg) cells, which are broadly classified as thymically derived (tTreg) or extrathymically induced (iTreg), suppress immune responses and display stringent dependence to the transcription factor Foxp3. However precise understanding of molecular events
that promote and preserve Foxp3 expression in Treg cells is still evolving. Here we show that Foxp1, a forkhead transcription factor and a sibling family member of Foxp3, is essential for sustaining optimal expression of Foxp3 specifically in iTreg cells. Deletion of Foxp1 renders
iTreg cells to gradually lose Foxp3, resulting in dramatically reduced Nrp1−Helios− iTreg compartment as well as augmented intestinal inflammation in aged mice. Our finding underscores a mechanistic module in which evolutionarily related transcription factors
establish a molecular program to ensure efficient immune homeostasis. Furthermore, it provides a novel target that can be potentially modulated to exclusively reinforce iTreg stability keeping their thymic counterpart unperturbed.