Murine autoantigen-specific type 1 regulatory T cells promote oligodendrogenesis through amphiregulin-EGFR signaling.

Abstract

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) that results from oligodendrocyte loss and multifocal demyelination of the CNS white matter. Current therapies can suppress the progression of CNS inflammation but do not actively promote tissue repair. Nanoparticles (NPs) coated with CNS-specific peptide-major histocompatibility complex class II (pMHCII) molecules can alleviate disability in mice with experimental autoimmune encephalomyelitis (EAE) by triggering the formation, expansion, and recruitment of antigen-specific type 1 regulatory CD4⁺ T cells (Tr1 cells). By investigating the effects of pMHCII-NP therapy on focal demyelinated lesions in the spinal cord induced by lysolecithin and sustained by chronic autoimmune encephalitogenic insults, here, we show that CNS antigen-specific Tr1 cells promote oligodendrogenesis, the preservation of axon caliber, and remyelination. Cell-specific deletion of <i>amphiregulin</i> (<i>Areg</i>) in T cells or of the <i>epidermal growth factor receptor</i> (<i>Egfr</i>) in oligodendrocytes abrogated these therapeutic outcomes. Oligodendrocyte-specific deletion of <i>Egfr</i> did not impair the pharmacodynamic or anti-inflammatory effects of pMHCII-NP treatment. These findings indicate that the oligodendrocyte-mediated therapeutic effects of pMHCII-NP treatment are dissociated from the anti-inflammatory properties of Tr1 cells; instead, they involve Tr1 cell-derived Areg to activate oligodendrocytes in an EGFR-dependent manner. Together, these results indicate that antigen-specific regulatory T cells can promote oligodendrogenesis and highlight the amphiregulin-oligodendrocyte EGFR pathway as a target for therapeutic intervention in MS.