A multiply redundant genetic switch 'locks in' the transcriptional signature of regulatory T cells

Transcription factor Foxp3 is essential for the development and function of regulatory T cells, but it does not act in isolation. Benoist and colleagues identify a quintet of factors that facilitate transcriptional regulation by Foxp3. The transcription factor Foxp3 participates dominantly in the specification and function of Foxp3+CD4+ regulatory T cells (Treg cells) but is neither strictly necessary nor sufficient to determine the characteristic Treg cell signature. Here we used computational network inference and experimental testing to assess the contribution of other transcription factors to this. Enforced expression of Helios or Xbp1 elicited distinct signatures, but Eos, IRF4, Satb1, Lef1 and GATA-1 elicited exactly the same outcome, acting in synergy with Foxp3 to activate expression of most of the Treg cell signature, including key transcription factors, and enhancing occupancy by Foxp3 at its genomic targets. Conversely, the Treg cell signature was robust after inactivation of any single cofactor. A redundant genetic switch thus 'locked in' the Treg cell phenotype, a model that would account for several aspects of Treg cell physiology, differentiation and stability.