Notch3 Directs a Regulatory T Cells-Microglia axis to Promote Autoimmune Neuroinflammation

Deciphering the mechanisms that promote central nervous system inflammation in multiple sclerosis is critical for developing precision therapies. We show that a specific regulatory T (Treg) cell subpopulation expressing Notch3 was increased in the peripheral blood and cerebrospinal fluid of individuals with multiple sclerosis (MS) and in the central nervous system (CNS) of mice with experimental autoimmune encephalomyelitis (EAE). Notch3 expression was upregulated by mechanisms involving the gut microbiota and Treg cell-specific toll-like receptor (TLR) signaling to promote EAE severity. Notch3 interaction with delta-like ligand 1 (DLL1) on microglia subverted Treg cells into T helper 17 (Th17) cells by Hippo pathway-dependent mechanisms while also inducing an inflammatory microglial response. Its deletion inhibited EAE by preventing Treg cell destabilization into Th17 cells while simultaneously promoting the expansion of a novel brain-protective neuropeptide receptor 1 (NPY1R)+ Treg cell population that suppressed pathogenic IFN+ and GM-CSF+ effector T cells. Our studies thus identify Notch3-mediated immune tolerance subversion as a fundamental mechanism that licenses autoimmune neuroinflammation.