Mus musculus Raw sequence reads

Although the master transcription factors are the key to the development of specific T cell subsets, whether additional transcriptional regulators are induced by the same stimuli that dominantly repress development of other T cell lineages have not been fully elucidated. Using Transforming growth factor-ß (TGF-ß) induced iTreg system, we set out to identify transcriptional regulators that would work together with Foxp3 but at the same time repress other T cell subsets to ensure unopposed development of iTregs. Here we show that Musculin (MSC, or ABF-1), a basic helix-loop-helix (bHLH) transcription factor, which is induced by Smad3 under TGF-ß stimulation, is not only critical for iTreg cell development but promotes development of iTregs by repressing the Th2 transcriptional program. Loss of MSC reduces Foxp3 expression and induces Th2 differentiation even under TGF-ß induced iTreg differentiation conditions. MSC mediates this effect by physically interacting with GATA3, by interrupting binding of GATA3 to the Th2 cytokine locus and by reducing intrachromosomal interactions within the Th2 cytokine gene cluster. iTregs from MSC-deficient mice are not able to suppress Th2 responses and the Msc–/– mice spontaneously develop gut and lung inflammation with age. Our data indicate that MSC enforces Foxp3 expression and promotes unidirectional induction of iTregs by repressing development of the Th2 developmental program.

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