Control of peripheral tolerance by regulatory T cell-intrinsic Notch signaling

Receptors of the Notch family direct the differentiation of helper T cell subsets, but their influence on regulatory T cell (T-reg cell) responses is obscure. We found here that lineage-specific deletion of components of the Notch pathway enhanced Treg cell mediated suppression of type 1 helper T cell (T(H)1 cell) responses and protected against their T(H)1 skewing and apoptosis. In contrast, expression in Tin cells of a gain-of-function transgene encoding the Notchl intracellular domain resulted in lymphoproliferation, exacerbated T(H)1 responses and autoimmunity. Cell-intrinsic canonical Notch signaling impaired Treg cell fitness and promoted the acquisition by Treg cells of a T(H)1 cell like phenotype, whereas non-canonical Notch signaling dependent on the adaptor Rictor activated the kinase AKT-transcription factor Foxo1 axis and impaired the epigenetic stability of Foxp3. Our findings establish a critical role for Notch signaling in controlling peripheral T-reg cell function.