Нотх3 дестабилизирует регулируемые Т клетки для аутоиммунной нейроинфламмации при множественном склерозе.
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Benamar Mehdi, Contini Paola, Schmitz-Abe Klaus, Lanzetta Olga, Getachew Feven, Bachelin Corinne, Leyva Castillo Juan Manuel, Wang Muyun, Oktelik Fatma Betul, Perrot Océane, Batamack Yvann, Arbag Sena Nur, Stephen-Victor Emmanuel, Harb Hani, Agrawal Pankaj B, Louapre Céline, Ivaldi Federico, Uccelli Antonio, Inglese Matilde, Angelini Claudia, Zujovic Violetta, De Palma Raffaele, Chatila Talal A
Аннотация
Оригинал публикации
Notch3 destabilizes regulatory T cells to 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 was increased in individuals with MS and in mice with experimental autoimmune encephalomyelitis (EAE). Notch3+ Treg cells were induced by the gut microbiota via Toll-like receptor (TLR)-dependent mechanisms. They then translocated to the central nervous system (CNS) in EAE where they promoted disease severity. Notch3 interacted with delta-like ligand 1 (DLL1) on microglia to subvert Treg cells into T helper 17 (Th17) cells. Notch3 deletion in Treg cells prevented EAE onset by stabilizing Treg cells and by simultaneously promoting the expansion of a tissue-resident Treg cell population that expressed neuropeptide Y receptor 1 (NPY1R) and which suppressed pathogenic IFN-γ+ and GM-CSF+ T cells. Our studies thus identify altered Treg cell population dynamics as a fundamental pathogenic mechanism in autoimmune neuroinflammation.