The transcription factor musculin promotes the unidirectional development of peripheral T cells by suppressing the T2 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 cells) induced by transforming growth factor-β (TGF-β), we identified the TF musculin (MSC) as being critical for the development of induced T cells (iT cells) by repression of the T helper type 2 (T2) transcriptional program. Loss of MSC reduced expression of the T cell master TF Foxp3 and induced T2 differentiation even under iT-cell-differentiation conditions. MSC interrupted binding of the TF GATA-3 to the locus encoding T2-cell-related cytokines and diminished intrachromosomal interactions within that locus. MSC-deficient (Msc) iT cells were unable to suppress T2 responses, and Msc mice spontaneously developed gut and lung inflammation with age. MSC therefore enforced Foxp3 expression and promoted the unidirectional induction of iT cells by repressing the T2 developmental program.