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.

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.

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

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.

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Anti-CD20 antibody (ab) treatment exhibits an unprecedented therapeutic benefit in multiple sclerosis (MS). The very fact that B cell depletion is effective in a disease that was generally considered T cell-driven was astonishing. In addition to the extensive analysis of B cells, it also led to the discovery and the consideration of CD20 + T cells in MS pathology. CD20 + T cells are described as a small population of T cells that is increased in autoimmune diseases such as MS, but little else is known. Therefore, we wanted to understand which role CD20 + T cells play in MS and dissect whether their depletion by anti-CD20 abs partakes in the positive therapeutic effect. We also wanted to analyze the origin of CD20 + T cells in MS and in experimental autoimmune encephalomyelitis (EAE) as our model system.In this context, we discovered and described CD20 + T cells in mice. Since we were unable to expand the CD20 + T cell population in vitro without B cell-dependent T cell activation, we ascertained that murine CD20 + T cells cannot endogenously express CD20. As a result, we examined the hypothesis of a trogocytotic transfer of CD20 from CD20-highly expressing B cells to T cells during antigen-dependent T cell-B cell interaction. We could demonstrate in various in vitro and in vivo experiments that trogocytosis is indeed the actual origin of CD20 + T cells in mice. These results suggest that CD20 on T cells could serve as a marker for T cell activation by B cells.In EAE mice, but also in MS patients, we could determine CD20 + T cells to be predominantly proinflammatory cells, which strongly express pathogenic attributes, promoting their potential relevance in MS development and progression. The expansion of CD20 + T cells in EAE mice and MS patients and their depletion with anti-CD20 antibodies in both species furthers the hypothesis of their pertinence in the disease.Ultimately, adoptive transfer experiments and the characterization of CD20 + T cells in greater detail strongly indicate their pathogenicity in EAE, respectively MS. coincide with inflammation and demyelination of the CNS that are discernible in MRI as MRI lesions 4 . Over time, the improvement after relapses, occurring in the remission phase can diminish and the patient gradually transitions into a more progressive disease course (SP) with proceeding disability 6 . At this stage, inflammatory lesions are no longer characteristic, and a progressive neurological decline is additionally accompanied by CNS atrophy. CNS atrophy is defined by decreased brain volume and increased axonal loss 4 . About 10 % of MS patients show a primarily progressive clinical course. This is generally diagnosed in older patients and considered more aggressive, with a faster decline, progression, and an relative absence of the RR stages characteristic for the primarily relapsing disease course 7 .Clinical symptoms of MS vary from fatigue, motor impairments, sensory and visual disturbances to pain and cognitive impairments. The specific symptoms in each patient are derived from ...