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Abstract Myelin regeneration (remyelination) is essential to prevent neurodegeneration in demyelinating diseases such as Multiple Sclerosis, however, its efficiency declines with age. Regulatory T cells (Treg) recently emerged as critical players in tissue regeneration, including remyelination. However, the effect of ageing on Treg-mediated regenerative processes is poorly understood. Here, we show that expansion of aged Treg does not rescue age-associated remyelination impairment due to an intrinsically diminished capacity of aged Treg to promote oligodendrocyte differentiation and myelination in male and female mice. This decline in regenerative Treg functions can be rescued by a young environment. We identified Melanoma Cell Adhesion Molecule 1 (MCAM1) and Integrin alpha 2 (ITGA2) as candidates of Treg-mediated oligodendrocyte differentiation that decrease with age. Our findings demonstrate that ageing limits the neuroregenerative capacity of Treg, likely limiting their remyelinating therapeutic potential in aged patients, and describe two mechanisms implicated in Treg-driven remyelination that may be targetable to overcome this limitation.

BackgroundThe extent of cortical pathology is an important determinant of multiple sclerosis (MS) severity. Cortical demyelination and neurodegeneration are related to inflammation of the overlying leptomeninges, a more inflammatory CSF milieu and with parenchymal microglia and astroglia activation. These are all components of the compartmentalised inflammatory response. Compartmentalised inflammation is a feature of progressive MS, which is not targeted by disease modifying therapies. Complement is differentially expressed in the MS CSF and complement, and complement receptors, are associated with demyelination and neurodegeneration.MethodsTo better understand if complement activation in the leptomeninges is associated with underlying cortical demyelination, inflammation, and microglial activation, we performed a neuropathological study of progressive MS (n = 22, 14 females), neuroinflammatory (n = 8), and non-neurological disease controls (n = 10). We then quantified the relative extent of demyelination, connective tissue inflammation, complement, and complement receptor positive microglia/macrophages.ResultsComplement was elevated at the leptomeninges, subpial, and within and around vessels of the cortical grey matter. The extent of complement C1q immunoreactivity correlated with connective tissue infiltrates, whilst activation products C4d, Bb, and C3b associated with grey matter demyelination, and C3a receptor 1+ and C5a receptor 1+ microglia/macrophages closely apposed C3b labelled cells. The density of C3a receptor 1+ and C5a receptor 1+ cells was increased at the expanding edge of subpial and leukocortical lesions. C5a receptor 1+ cells expressed TNFα, iNOS and contained puncta immunoreactive for proteolipid protein, neurofilament and synaptophysin, suggesting their involvement in grey matter lesion expansion.InterpretationThe presence of products of complement activation at the brain surfaces, their association with the extent of underlying pathology and increased complement anaphylatoxin receptor positive microglia/macrophages at expanding cortical grey matter lesions, could represent a target to modify compartmentalised inflammation and cortical demyelination.

Abstract 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.

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.