The transcription factor musculin promotes the unidirectional development of peripheral T reg cells by suppressing the T H 2 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 (T reg cells) induced by transforming growth factor-β (TGF-β), we identified the TF musculin (MSC) as being critical for the development of induced T reg cells (iT reg cells) by repression of the T helper type 2 (T H 2) transcriptional program. Loss of MSC reduced expression of the T reg cell master TF Foxp3 and induced T H 2 differentiation even under iT reg -cell-differentiation conditions. MSC interrupted binding of the TF GATA-3 to the locus encoding T H 2-cell-related cytokines and diminished intrachromosomal interactions within that locus. MSC-deficient (Msc -/-) iT reg cells were unable to suppress T H 2 responses, and Msc -/- mice spontaneously developed gut and lung inflammation with age. MSC therefore enforced Foxp3 expression and promoted the unidirectional induction of iT reg cells by repressing the T H 2 developmental program.