The transcription factor musculin promotes the unidirectional development of peripheral Treg cells by suppressing the TH2 transcriptional program.

Although master transcription factors (TFs) are key to the development of specific T cell subsets, whether additional transcriptional regulators are induced by the same stimuli that dominantly repress the development of other, non-specific T cell lineages has not been fully elucidated. Through the use of regulatory T cells (Treg cells) induced by transforming growth factor-β (TGF-β), we identified the TF musculin (MSC) as being critical for the development of induced Treg cells (iTreg cells) by repression of the T helper type 2 (TH2) transcriptional program. Loss of MSC reduced expression of the Treg cell master TF Foxp3 and induced TH2 differentiation even under iTreg-cell-differentiation conditions. MSC interrupted binding of the TF GATA-3 to the locus encoding TH2-cell-related cytokines and diminished intrachromosomal interactions within that locus. MSC-deficient (Msc-/-) iTreg cells were unable to suppress TH2 responses, and Msc-/- mice spontaneously developed gut and lung inflammation with age. MSC therefore enforced Foxp3 expression and promoted the unidirectional induction of iTreg cells by repressing the TH2 developmental program.