Year: 2025
Type: article
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)
Source: The Journal of Immunology
Authors: Mehdi Benamar, Paola Contini, Klaus Schmitz-Abe, Corinne Bachelin, Olga Lanzetta, Manuel Leyva Castillo, Muyun Wang, Fatma B Oktelik, Océane Perrot, Sena Nur Arbag, Emmanuel Stephen Victor, Hani Harb, Céline Louapre, Federico Ivaldi, Antonio Uccelli, Matilde Inglese, Claudia Angelini, Violetta Zujovic, Raffaele De Palma, Talal A Chatila
Institutions: Boston Children's Hospital, Harvard University, Ospedale Policlinico San Martino, University of Genoa, Centre National de la Recherche Scientifique, Inserm, Sorbonne Université, Institut du Cerveau, Institute of Genetics and Biophysics, National Research Council, Pitié-Salpêtrière Hospital, University of Utah, Huntsman Cancer Institute, Technische Universität Dresden, Istituto per le Applicazioni del Calcolo Mauro Picone
Language: English
Subfield: Pathology and Forensic Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4416447162