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

Notch receptors direct the differentiation of T helper (T(H)) cell subsets, but their influence on regulatory T (T(reg)) cell responses is obscure. We here report that lineage-specific deletion of components of the Notch pathway enhanced T(reg) cell-mediated suppression of T(H)1 responses, and protected against their T(H)1 skewing and apoptosis. Expression in T(reg) cells of gain of function transgene encoding Notch1 intracellular domain resulted in lymphoproliferation, exacerbated T(H)1 responses and autoimmunity. Cell-intrinsic canonical Notch signaling impaired T(reg) cell fitness, promoted the acquisition by T(reg) cells of a T(H)1 cell-like phenotype, whereas Rictor-dependent non-canonical Notch signaling activated the AKT-Foxo1 axis and impaired Foxp3 epigenetic stability. These findings establish a critical role for Notch signaling in controlling peripheral T(reg) cell functions.