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Multiple sclerosis (MS) is a common and devastating chronic inflammatory disease of the CNS. CD4+ T cells are assumed to be the first to cross the blood–central nervous system (CNS) barrier and trigger local inflammation. Here, we explored how pathogenicity‐associated effector programs define CD4+ T cell subsets with brain‐homing ability in MS. Runx3‐ and Eomes‐, but not T‐bet‐expressing CD4+ memory cells were diminished in the blood of MS patients. This decline reversed following natalizumab treatment and was supported by a Runx3+Eomes+T‐bet− enrichment in cerebrospinal fluid samples of treatment‐naïve MS patients. This transcription factor profile was associated with high granzyme K (GZMK) and CCR5 levels and was most prominent in Th17.1 cells (CCR6+CXCR3+CCR4−/dim). Previously published CD28− CD4 T cells were characterized by a Runx3+Eomes−T‐bet+ phenotype that coincided with intermediate CCR5 and a higher granzyme B (GZMB) and perforin expression, indicating the presence of two separate subsets. Under steady‐state conditions, granzyme Khigh Th17.1 cells spontaneously passed the blood–brain barrier in vitro. This was only found for other subsets including CD28− cells when using inflamed barriers. Altogether, CD4+ T cells contain small fractions with separate pathogenic features, of which Th17.1 seems to breach the blood–brain barrier as a possible early event in MS. [ABSTRACT FROM AUTHOR]

Background: In multiple sclerosis (MS), B cells are considered main triggers of the disease, likely as the result of complex interaction between genetic and environmental risk factors. Studies on monozygotic twins discordant for MS offer a unique way to reduce this complexity and reveal discrepant subsets., Methods: In this study, we analyzed B cell subsets in blood samples of monozygotic twins with and without MS using publicly available data. We verified functional characteristics by exploring the role of therapy and performed separate analyses in unrelated individuals., Findings: The frequencies of CXCR3 + memory B cells were reduced in the blood of genetically identical twins with MS compared to their unaffected twin siblings. Natalizumab (anti-VLA-4 antibody) was the only treatment regimen under which these frequencies were reversed. The CNS-homing features of CXCR3 + memory B cells were supported by elevated CXCL10 levels in MS cerebrospinal fluid and their in vitro propensity to develop into antibody-secreting cells., Conclusions: Circulating CXCR3 + memory B cells are affected by non-heritable cues in people who develop MS. This underlines the requirement of environmental risk factors such as Epstein-Barr virus in triggering these B cells. We propose that after CXCL10-mediated entry into the CNS, CXCR3 + memory B cells mature into antibody-secreting cells to drive MS., Funding: This work was supported by Nationaal MS Fonds (OZ2021-016), Stichting MS Research (19-1057 MS, 20-490f MS, and 21-1142 MS), the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program grant agreement no. 882424, and the Swiss National Science Foundation (733 310030_170320, 310030_188450, and CRSII5_183478)., Competing Interests: Declaration of interests J.S. received lecture and/or consultancy fees from Biogen, Merck, Novartis, and Sanofi Genzyme. M.M.v.L. received research support from EMD Serono, Merck, GSK, Novartis, and Idorsia Pharmaceuticals, Ltd. L.A.G. has received speaker honoraria, personal fees for advisory boards, or research funding from Roche Pharma, Teva, Biogen, and Merck Healthcare GmbH., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Multiple sclerosis (MS) is a common and devastating chronic inflammatory disease of the CNS. CD4 + T cells are assumed to be the first to cross the blood-central nervous system (CNS) barrier and trigger local inflammation. Here, we explored how pathogenicity-associated effector programs define CD4 + T cell subsets with brain-homing ability in MS. Runx3- and Eomes-, but not T-bet-expressing CD4 + memory cells were diminished in the blood of MS patients. This decline reversed following natalizumab treatment and was supported by a Runx3 + Eomes + T-bet - enrichment in cerebrospinal fluid samples of treatment-naïve MS patients. This transcription factor profile was associated with high granzyme K (GZMK) and CCR5 levels and was most prominent in Th17.1 cells (CCR6 + CXCR3 + CCR4 -/dim ). Previously published CD28 - CD4 T cells were characterized by a Runx3 + Eomes - T-bet + phenotype that coincided with intermediate CCR5 and a higher granzyme B (GZMB) and perforin expression, indicating the presence of two separate subsets. Under steady-state conditions, granzyme K high Th17.1 cells spontaneously passed the blood-brain barrier in vitro. This was only found for other subsets including CD28 - cells when using inflamed barriers. Altogether, CD4 + T cells contain small fractions with separate pathogenic features, of which Th17.1 seems to breach the blood-brain barrier as a possible early event in MS., (© 2023 The Authors. European Journal of Immunology published by Wiley-VCH GmbH.)

The anti-CD20 monoclonal antibody ocrelizumab reduces disability progression in primary progressive multiple sclerosis. CD20 is a prototypical B-cell marker; however, subpopulations of CD4 + and CD8 + T cells in peripheral blood and cerebrospinal fluid also express low levels of CD20 (CD20 dim ). Therefore, direct targeting and depletion of these CD20 dim T-cell subpopulations may contribute to the therapeutic effect of ocrelizumab. The aim of this observational cohort study was to compare CD20 + B-cell and CD20 dim T-cell distributions between peripheral blood and cerebrospinal fluid of ocrelizumab-treated or ocrelizumab-untreated people with primary progressive multiple sclerosis. Ocrelizumab treatment was associated with depletion of circulating B cells and CD20 dim CD4 + and CD20 dim CD8 + T cells ( P < 0.0001, P = 0.0016 and P = 0.0008, respectively) but, in cerebrospinal fluid, only with lower proportions of B cells and CD20 dim memory CD4 + T cells ( P < 0.0001 and P = 0.0043, respectively). The proportional prevalence of cerebrospinal fluid CD20 dim memory CD8 + T cells was not significantly reduced ( P = 0.1333). Only in cerebrospinal fluid, the proportions of CD20 dim cells within CD4 + and not CD8 + T cells positive for CCR5, CCR6 and CXCR3 were reduced in ocrelizumab-treated participants. The proportion of CD20 dim CD4 + T cells and abundance of CD4 + relative to CD8 + T cells in cerebrospinal fluid correlated positively with age ( R = 0.6799, P = 0.0150) and Age-Related Multiple Sclerosis Severity score ( R = 0.8087, P = 0.0014), respectively. We conclude that, in contrast to cerebrospinal fluid CD20 dim CD8 + T cells, B cells and CD20 dim CD4 + T cells are reduced in cerebrospinal fluid of people with primary progressive multiple sclerosis with an ocrelizumab-associated depletion of circulating B cells and CD20 dim T cells. Therefore, these cells are likely to contribute to the therapeutic effects of ocrelizumab in people with primary progressive multiple sclerosis., Competing Interests: M.M.v.L. received research support from EMD Serono, Merck, GSK and Idorsia Pharmaceuticals Ltd. J.S. received lecture and/or consultancy fees from Biogen, Merck, Novartis, Roche and Sanofi-Genzyme. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)