Antigen-specific Tr1 cells promote oligodendrogenesis and remyelination in MS via amphiregulin-EGFR signaling.

Multiple sclerosis (MS) is a debilitating autoimmune disease characterized by oligodendrocyte loss and demyelination in the central nervous system (CNS). Current therapies primarily suppress inflammation, but they fall short in actively promoting tissue repair and remyelination, leaving a critical gap in treating disease progression. Antigen-specific therapies, such as nanoparticles coated with CNS-specific peptide-MHCII (pMHCII-NPs), offer a promising avenue by selectively modulating autoreactive immune responses and inducing type 1 regulatory T cells (Tr1 cells) to address this unmet need.

Researchers investigated the effects of pMHCII-NP therapy in a murine model of experimental autoimmune encephalomyelitis (EAE), specifically focusing on focal demyelinated lesions in the spinal cord induced by lysolecithin. Mice received chronic autoimmune encephalitogenic insults to sustain the disease. The study utilized genetic models with cell-specific deletion of amphiregulin (Areg) in T cells and epidermal growth factor receptor (Egfr) in oligodendrocytes to dissect the molecular mechanisms. Primary endpoints included assessment of oligodendrogenesis, preservation of axon caliber, and remyelination in the CNS lesions.

CNS antigen-specific Tr1 cells were found to actively promote oligodendrogenesis, preserve axon caliber, and facilitate remyelination in the demyelinated lesions. This therapeutic effect was critically dependent on specific signaling pathways. > Cell-specific deletion of amphiregulin (Areg) in T cells or epidermal growth factor receptor (Egfr) in oligodendrocytes completely abrogated these beneficial outcomes, indicating a direct role for Tr1 cell-derived Areg in activating oligodendrocyte EGFR. Importantly, oligodendrocyte-specific deletion of Egfr did not impair the pharmacodynamic or anti-inflammatory effects of pMHCII-NP treatment, demonstrating that the oligodendrocyte-mediated repair mechanisms are distinct from the anti-inflammatory properties of Tr1 cells. These findings highlight a novel, direct pro-repair pathway.