Notch3+ regulatory T cells drive autoimmune neuroinflammation in multiple sclerosis 2040

Abstract Description Multiple sclerosis (MS) is a chronic autoimmune neuroinflammatory disease that exacts a heavy burden of morbidity and incapacity. Its persistence despite countervailing immunoregulatory constraints, most notably those imposed by Regulatory T (Treg) cells, suggests disease-associated mechanisms that subvert those constraints. Of particular interest is the role of Notch signaling in Treg cells as a disease mechanism in MS. The present studies were undertaken to identify the Notch receptors involved in MS/EAE pathogenesis, and the mechanisms by which they disable immune tolerance. A specific Treg cell subpopulation expressing Notch3 was found increased in peripheral blood and the cerebrospinal fluid T lymphocytes of patients with MS and in mice with experimental autoimmune encephalomyelitis (EAE). Notch3 was induced by the gut microbiota through a TLR-dependent mechanisms to promote EAE severity. Notch3 interacted with delta-like ligand 1 (DLL1) on microglia to subvert Treg cells into Th17 cells. Treg cell-specific Notch3 deletion inhibited EAE by preventing Hippo pathway-dependent 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 identify Notch3-mediated immune tolerance subversion as a fundamental disease-driving mechanism that licenses brain tissue inflammation in autoimmunity. Funding Sources This work was supported by National Institutes of Health (NIH) grants R01 AI115699, R01 AI065617, and R01 AI06561720S1 to T.A.C and M.B was supported by a grant from the Office of Faculty Development at Boston Children’s Hospital. Topic Categories Neuroimmunology (NEUR)