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.

Pathogenic mechanisms of T cells in several central nervous system (CNS) disorders are well-established. However, more recent studies have uncovered compelling beneficial roles of T cells in neurological diseases, ranging from tissue protection to regeneration. These divergent functions arise due to the diversity of T cell subsets, particularly CD4+ T cells. Here, we review the beneficial impact of T cell subsets in a range of neuroinflammatory and neurodegenerative diseases including multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, stroke, and CNS trauma. Both T cell-secreted mediators and direct cell contact-dependent mechanisms deliver neuroprotective, neuroregenerative and immunomodulatory signals in these settings. Understanding the molecular details of these beneficial T cell mechanisms will provide novel targets for therapeutic exploitation that can be applied to a range of neurological disorders.

Little is known about how the hemispheres interact in processing of stimuli presented at vertical midline. Processing might be mutually independent or cooperative. Here we measured target identification and visually evoked EEG potentials while stimulus streams containing two targets, T1 and T2, were either presented at vertical midline above and below fixation, or laterally, left and right. With left and right streams, potentials evoked by filler stimuli and by T2 were earlier at the right than the left visual cortex, and T2 was better identified left than right, confirming earlier results and suggesting better capabilities of the right hemisphere in this task. With streams above and below fixation, EEG potentials evoked by filler stimuli and by T2 were likewise earlier at the right than the left hemisphere, and T2 was generally identified as well as, but not better than left T2, in one target constellation even worse (T2 in lower stream preceded by T1 in upper stream). These results suggest right-hemisphere preference for this task even with stimuli at vertical midline, and no added value through hemispheric cooperation. Lacking asymmetry for T1 amidst asymmetries for filler stimuli and for T2 might indicate alternating access of the hemispheres to midline stimuli as one means of hemispheric division of labor.

One of the unmet clinical needs in demyelinating diseases such as Multiple Sclerosis (MS) is to provide therapies that actively enhance the process of myelin regeneration (remyelination) in the central nervous system (CNS). Oligodendrocytes, the myelinating cells of the CNS, play a central role in remyelination and originate from oligodendrocyte progenitor cells (OPCs). We recently showed that depletion of regulatory T cells (Treg) impairs remyelination in vivo, and that Treg-secreted factors directly enhance oligodendrocyte differentiation. Here we aim to further characterize the dynamics of Treg-enhanced oligodendrocyte differentiation as well as elucidate the cellular components of a murine mixed neuron-glia model.Murine mixed neuron-glia cultures were generated from P2–7 C57BL/6 mice and characterized for percentage of neuronal and glial cell populations prior to treatment at 7 days in vitro (div) as well as after treatment with Treg-conditioned media at multiple timepoints up to 12 div.Mixed neuron-glia cultures consisted of approximately 30% oligodendroglial lineage cells, 20% neurons and 10% microglia. Furthermore, a full layer of astrocytes, that could not be quantified, was present. Treatment with Treg-conditioned media enhanced the proportion of MBP+ oligodendrocytes and decreased the proportion of PDGFRα+ OPCs, but did not affect OPC proliferation or survival. Treg-enhanced oligodendrocyte differentiation was not caused by Treg polarizing factors, was dependent on the number of activation cycles Treg underwent and was robustly achieved by using 5% conditioned media.These studies provide in-depth characterization of a murine mixed neuron-glia model as well as further insights into the dynamics of Treg-enhanced oligodendrocyte differentiation.Electronic supplementary materialThe online version of this article (10.1186/s13041-018-0367-6) contains supplementary material, which is available to authorized users.

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