The lack of therapies for progressive multiple sclerosis highlights the need to understand the regenerative process of remyelination that can follow CNS demyelination. This involves an innate immune response consisting of microglia/macrophages, which can be polarized to distinct functional phenotypes: proinflammatory (M1) or anti-inflammatory/immunoregulatory (M2). Here we show that a switch from an M1-to M2-dominant response occurred within microglia and peripherally-derived macrophages as remyelination started. Oligodendrocyte differentiation was enhanced in vitro with M2 conditioned media, and impaired in vivo following intra-lesional M2 depletion. M2 densities were increased in lesions of aged mice in which remyelination was enhanced by parabiotic coupling to a younger animal, and in MS lesions that normally show remyelination. Blocking M2-derived activin-A inhibited oligodendrocyte differentiation during remyelination in cerebellar slice cultures. Our results therefore show that M2 polarization is essential for efficient remyelination and identify activin-A as a novel therapeutic target for CNS regeneration.Remyelination, the formation of myelin sheaths around demyelinated axons by newly differentiated oligodendrocytes, can occur efficiently following central nervous system (CNS) demyelination. A major component of this regenerative process is a robust innate immune response consisting of peripherally-derived macrophages and their CNS-resident counterparts, microglia. Although these microglia/macrophages are implicated in CNS autoimmune disease via secretion of toxic molecules 1 and antigen presentation to cytotoxic lymphocytes 2 , they also exhibit regenerative properties through the phagocytosis of myelin debris 3, 4 and secretion of growth/neurotrophic factors 5 . Regenerative properties of Corresponding author: Veronique E. Miron, MRC Centre for Regenerative Medicine, The University of Edinburgh, Edinburgh BioQuarter, 5 Little France Drive, Edinburgh, EH16 4UU, Tel: +44 (0) 131 651 9570, Fax: +44 (0) 131 651 9501, vmiron@staffmail.ed.ac.uk. Author Contributions: V.M. conceived the project, designed and carried out experiments, performed data acquisition, quantification, and analysis, and wrote the manuscript; A.B. and A.W. assisted in in vivo studies, and A.W. assisted in data interpretation; J.-W.Z. contributed to analysis and quantification of parabiosis lesion tissue; A.B., A.W., T.Y., and P.v.W. performed lesioning experiments to provide lesion tissue and assisted in tissue selection; J.R., J.S., A.J.W, R.J.M.F. provided parabiosis lesion tissue; R.J.M.F. assisted in study design, data interpretation, and manuscript writing; C.ff.-C. supervised the project, assisted in study design, data interpretation, figure preparation, and writing of the manuscript. Europe PMC Funders GroupAuthor Manuscript Nat Neurosci. Author manuscript; available in PMC 2014 April 07. Published in final edited form as:Nat Neurosci. 2013 September ; 16(9): 1211-1218. doi:10.1038/nn.3469. Europe PMC Funders Author Manus...

Regeneration of central nervous system (CNS) myelin involves differentiation of oligodendrocytes from oligodendrocyte progenitor cells (OPC). In multiple sclerosis (MS), remyelination can fail despite abundant OPC, suggesting impairment of oligodendrocyte differentiation. T cells infiltrate the CNS during MS, yet little is known about T cell functions in remyelination. Here, we report that regulatory T cells (Treg) promote oligodendrocyte differentiation and (re)myelination. Treg-deficient mice exhibited significantly impaired remyelination and oligodendrocyte differentiation that was rescued by adoptive transfer of Treg. In brain slice cultures, Treg accelerated developmental myelination and remyelination, even in the absence of overt inflammation. Treg directly promoted OPC differentiation and myelination in vitro. We identified CCN3 as a novel Treg-derived mediator of oligodendrocyte differentiation and myelination in vitro. These findings reveal a new regenerative function of Treg in the CNS, distinct from immunomodulation. Although originally named ‘Treg’ to reflect immunoregulatory roles, this also captures emerging, regenerative Treg functions aptly.