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

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... 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 the location of the MS lesion in the brain and/or spinal cord 1 . Lesions are caused by immune cells crossing the blood-brain barrier, accumulating and attacking the CNS. Therefore, lesions are considered a hallmark of MS and are widely used as diagnostic criterion 4 . Fig.3: T cell subtypes Naïve CD4 + T cells can differentiate into various T helper cells: proinflammatory IFNγ-, TNFα-and GM-CSFcytokine expressing CXCR3 + Tbet + Th1, anti-inflammatory IL-4 and IL-10-expressing CCR4 + GATA3 + Th2, proinflammatory IL-17-expressing RORγt + Th17 or anti-inflammatory TGF-β and IL-10-expressing CD25 + Foxp3 + Treg cells. Naïve CD8 + T cell can differentiate into various cytotoxic T cells: proinflammatory CXCR3 + IFNγ-, TNFα-and GM-CSF-expressing Tc1, proinflammatory IL-17-expressing Tc17 or antiinflammatory IL-4-expressing Tc2 cells. percentage of IL-17-producing Th17 cells co-expressed CD20 119 . Since IL-17 55, 120, 121 , as well as IFNγ 41, 48 and TNFα 17, 122 , are known to play a considerable role in the development and progression of these autoimmune diseases, CD20 + T cells are considered as an important part in autoimmune disease development and progression. Since anti-CD20 ab treatment was shown to have a substantial therapeutic effect in rheumatoid arthritis and especially in MS 105, 108, 110, 123, 124 . Anti-CD20 abs could also be determined to deplete CD20 + T cells 116, 117, 125 , particularly activated, myelin-specific CD20 + T cells 91 . These findings raised the question, if the depletion of CD20 + T cells plays a considerable role in the positive treatment effect of anti-CD20 ab therapy 126 .