Proinflammatory CD20+ T cells contribute to CNS-directed autoimmunity.

The origin and function of CD20+ T cells are poorly understood. Here, we characterized CD20+ T cells in mice and humans and investigated how they are affected by anti-CD20 antibody treatment. We report that murine CD20+ T cells are unable to endogenously express the B cell lineage marker CD20; the development of CD20+ T cells in rodents requires the presence of CD20-expressing B cells. Our results demonstrated that both murine and human T cells acquire CD20 from B cells via trogocytosis while being activated by an antigen-presenting B cell. In patients with multiple sclerosis (MS) and mice with experimental autoimmune encephalomyelitis (EAE), expression of CD20 on T cells is associated with an up-regulation of activation markers, proinflammatory cytokines, and adhesion molecules, suggesting high pathogenic potential. Supporting this hypothesis, CD20+ T cells expand during active EAE in rodents; furthermore, adoptive transfer of CD20+ T cells into EAE-diseased mice worsened histological and clinical severity. Of direct therapeutic relevance, we demonstrate that the exclusive therapeutic elimination of CD20+ T cells effectively ameliorates EAE, independent of B cells. The results support the hypothesis that CD20+ T cells arise upon B cell-T cell interaction and that depletion of CD20+ T cells might contribute to the success of anti-CD20 antibody therapies in MS and other inflammatory disorders.

Proinflammatory CD20+ T Cells are Differentially Affected by Multiple Sclerosis Therapeutics.

The frequency of CD20+ T cells was reported to be increased in several inflammatory conditions. We report that in patients with multiple sclerosis (MS), CD20+ T cells display a distinct proinflammatory phenotype with pathogenic properties. Anti-CD20 treatment virtually extinguished CD20+ T cells, which might explain its broad effectiveness. Dimethyl fumarate dampened activity of differentiated CD20+ T cells, whereas fingolimod reduced their abundance only as part of its overall T cell suppressive capacity. Natalizumab increased the frequency of CD20+ effector T cells. Widely used MS therapeutics affect this proinflammatory T cell subset with assumed pathogenic potential in a surprisingly differential manner. ANN NEUROL 2021 ANN NEUROL 2021;90:834-839.

Neural Progenitor Cell-Derived Extracellular Vesicles Enhance Blood-Brain Barrier Integrity by NF-κB (Nuclear Factor-κB)-Dependent Regulation of ABCB1 (ATP-Binding Cassette Transporter B1) in Stroke Mice.

OBJECTIVE: Extracellular vesicles (EVs) derived from neural progenitor cells enhance poststroke neurological recovery, albeit the underlying mechanisms remain elusive. Since previous research described an enhanced poststroke integrity of the blood-brain barrier (BBB) upon systemic transplantation of neural progenitor cells, we examined if neural progenitor cell-derived EVs affect BBB integrity and which cellular mechanisms are involved in the process. Approach and Results: Using in vitro models of primary brain endothelial cell (EC) cultures as well as co-cultures of brain ECs (ECs) and astrocytes exposed to oxygen glucose deprivation, we examined the effects of EVs or vehicle on microvascular integrity. In vitro data were confirmed using a mouse transient middle cerebral artery occlusion model. Cultured ECs displayed increased ABCB1 (ATP-binding cassette transporter B1) levels when exposed to oxygen glucose deprivation, which was reversed by treatment with EVs. The latter was due to an EV-induced inhibition of the NF-κB (nuclear factor-κB) pathway. Using a BBB co-culture model of ECs and astrocytes exposed to oxygen glucose deprivation, EVs stabilized the BBB and ABCB1 levels without affecting the transcellular electrical resistance of ECs. Likewise, EVs yielded reduced Evans blue extravasation, decreased ABCB1 expression as well as an inhibition of the NF-κB pathway, and downstream matrix metalloproteinase 9 (MMP-9) activity in stroke mice. The EV-induced inhibition of the NF-κB pathway resulted in a poststroke modulation of immune responses. CONCLUSIONS: Our findings suggest that EVs enhance poststroke BBB integrity via ABCB1 and MMP-9 regulation, attenuating inflammatory cell recruitment by inhibition of the NF-κB pathway. Graphic Abstract: A graphic abstract is available for this article.

Dimethyl fumarate impairs differentiated B cells and fosters central nervous system integrity in treatment of multiple sclerosis.

In multiple sclerosis (MS), the effect of dimethyl fumarate (DMF) treatment is primarily attributed to its capacity to dampen pathogenic T cells. Here, we tested whether DMF also modulates B cells, which are newly recognized key players in MS, and to which extent DMF restricts ongoing loss of oligodendrocytes and axons in the central nervous system (CNS). Therefore, blood samples and brain tissue from DMF-treated MS patients were analyzed by flow cytometry or histopathological examination, respectively. Complementary mechanistic studies were conducted in inflammatory as well as non-inflammatory CNS demyelinating mouse models. In this study, DMF reduced the frequency of antigen-experienced and memory B cells and rendered remaining B cells less prone to activation and production of pro-inflammatory cytokines. Dissecting the functional consequences of these alterations, we found that DMF ameliorated a B cell-accentuated experimental autoimmune encephalomyelitis model by diminishing the capacity of B cells to act as antigen-presenting cells for T cells. In a non-inflammatory model of toxic demyelination, DMF limited oligodendrocyte apoptosis, promoted maturation of oligodendrocyte precursors and reduced axonal damage. In a CNS biopsy of a DMF-treated MS patient, we equivalently observed higher numbers of mature oligodendrocytes as well as a reduced extent of axonal damage when compared to a cohort of treatment-naïve patients. In conclusion, we showed that besides suppressing T cells, DMF dampens pathogenic B cell functions, which probably contributes to its clinical effectiveness in relapsing MS. DMF treatment may furthermore limit chronically ongoing CNS tissue damage, which may reduce long-term disability in MS apart from its relapse-reducing capacity.