Regulatory B Cells Normalize CNS Myeloid Cell Content in a Mouse Model of Multiple Sclerosis and Promote Oligodendrogenesis and Remyelination

Abstract

The unmet medical need of patients with multiple sclerosis (MS) is the inexorable loss of CNS myelin and latterly neurons leading to permanent neurologic disability. Solicitation of endogenous oligodendrocytes progenitor cells, the precursor of oligodendrocytes, to remyelinate axons may abort the onset of disability. In female mice with experimental autoimmune encephalomyelitis (EAE), a murine model of MS, adoptive transfer of IL-10⁺ regulatory B cells (B_regs) has been shown to reverse EAE by promoting the expansion of peripheral and CNS-infiltrating IL-10⁺ T cells. Here, we examined whether B_regs treatment and its bystander effect on regulatory T cells are associated with CNS repair as reflected by oligodendrogenesis and remyelination. We have found that transfusion of B_regs reverses established clinical EAE and that clinical improvement is associated with a significant increase in spinal cord remyelination as reflected by g-ratio analysis within the thoracic and lumbar spine. We further observed in the spinal cords of EAE B_regs-treated mice that CNS resident CD11b/CD45^intLy6C^- microglia, and infiltrating CD11b⁺/CD45^high monocytes/macrophages content reverts to normal and polarize to a M2-like CD206⁺ phenotype. Concurrently, there was a substantial increase in neo-oligodendrogenesis as manifest by an increase in CD45^-/low CNS cells expressing A2B5, an early marker in oligodendrocytes progenitor cell differentiation as well as GalC⁺/O1⁺ premyelinating and myelin basic protein⁺/myelin oligodendrocyte glycoprotein⁺ mature oligodendrocytes with reciprocal downregulation of paired related homeobox protein 1. These results demonstrate that the clinical benefit of B_regs is associated with normalization of CNS immune milieu and concurrent activation of oligodendrocyte progenitor cells with subsequent remyelination.SIGNIFICANCE STATEMENT In multiple sclerosis patients, demyelination progresses with aging and disease course, leading to irreversible disability. In this study, we have discovered, using a mouse model of multiple sclerosis, that the transfusion of autologous regulatory B cells (B_regs) is able to ameliorate, cure, and sustain the durable remission of the disease. We show that the adoptive transfer of B_regs dramatically decreased the frequency of myeloid-derived cells, both infiltrating monocytes/macrophages and resident microglia, and converted their phenotype to an immunosuppressive-like phenotype. Moreover, we showed that CNS oligodendrocyte progenitor cells are activated following B_regs treatment and differentiate into myelinating oligodendrocytes, which results in neo-oligodendrogenesis and remyelination of spinal cords.

Keywords: Bregs; myelin; oligodendrocytes; remyelination.