GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE316nnn/GSE316688/primaryOK200TranscriptomicsHomo sapiens OtherExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE316688GEOGSEfalseMultimodal discovery of a pathogenic B cell-dependent T cell state in multiple sclerosisB cell depleting therapies in multiple sclerosis (MS) have transformed disease management, yet the immunological mechanisms linking B cells to chronic compartmentalised CNS inflammation, the key pathological driver of disability accrual, remain poorly defined. Here, we leverage anti-CD20 therapy as an in vivo perturbational probe to disentangle MS immunobiology. We combine longitudinal, high-dimensional multimodal immune profiling in patients initiating ocrelizumab with a novel machine learning pipeline to resolve treatment-induced shifts in continuous immune cell states, revealing treatment-associated modulation of shared biological processes that act across the boundaries of discretely partitioned cell types. We identify a distinct chronically activated, proinflammatory–cytotoxic T cell state with CNS-homing properties that is selectively depleted following B cell ablation. Importantly, across independent datasets, the same T cell state is enriched in the circulation of patients with clinically aggressive relapsing disease, in CSF-enriched expanded clonotypes, including a subset with proven Epstein–Barr virus-specificity, and in chronically inflamed lesion rims in end-stage MS. Finally, we demonstrate that blockade of lymphocyte trafficking across the blood–brain barrier with the anti-integrin α4 therapy natalizumab leads to enrichment of this cell state in the circulation, demonstrating a mechanistically concordant effect across distinct high-efficacy MS therapies. Together, our findings support a B cell-dependent, pathogenic T cell state which links peripheral immune activation to CNS-compartmentalised smouldering neuroinflammation across disease stages. Direct therapeutic manipulation of this T cell state may represent a key opportunity for targeting chronic neuroinflammation and facilitate a strategic shift away from broad immune cell ablation.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 sapiens[42714077]