Notch3+ Regulatory T cells Drive Autoimmune Neuroinflammation in Multiple Sclerosis

The immune regulatory defects that promote neuroinflammation in multiple sclerosis (MS) remain unclear. We show that a specific regulatory T (Treg) cell subpopulation expressing Notch3 is increased in individuals with MS and in mice with experimental autoimmune encephalomyelitis (EAE). Notch3 is induced by the gut microbiota by toll-like receptor (TLR)-dependent mechanisms to promote EAE severity. Notch3 interacts with delta-like ligand 1 (DLL1) on microglia to subvert Treg cells into T helper 17 (Th17) cells. Notch3 Treg-specific deletion inhibits EAE by preventing Treg cell destabilization while simultaneously promoting the expansion of a novel tissue-resident neuropeptide receptor 1 (NPY1R)+ Treg cell population that suppressed pathogenic IFNg+ and GM-CSF+ T cells. Our studies thus identify altered Treg cell population dynamics as a fundamental pathogenic mechanism in autoimmune neuroinflammation. Overall design: We perfromed an ScRNA-seq on CNS CD4 cells from Foxp3YFPCRE and Foxp3YFPcre NOtch3Fl/Fl mice post EAE induction