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

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.