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

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Abstract
B-cell-depleting therapies in multiple sclerosis (MS) have transformed disease management, yet the immunological mechanisms linking B cells to chronic compartmentalized 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-compartmentalized smouldering neuroinflammation across disease stages. Direct therapeutic manipulation of this T-cell state might represent a key opportunity for targeting chronic neuroinflammation and facilitate a strategic shift away from broad immune cell ablation.
Funding Information
  • Aims2Cure (HMD00630)
  • Oak Foundation (OFIL-22-254)
  • Medical Research Council (MC_UU_00036/3)
  • Association of British Neurologists
  • Guarantors of Brain (HMR04540)

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