Multimodal discovery of a pathogenic B-cell-dependent T-cell state in multiple sclerosis

B 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.