Identifying CNS-colonizing T cells as potential therapeutic targets to prevent progression of multiple sclerosis

Multiple sclerosis (MS), an autoimmune disease of the central nervous system (CNS), can be suppressed in its early stages but eventually becomes clinically progressive and unresponsive to therapy. Here, we investigate whether the therapeutic resistance of progressive MS can be attributed to chronic immune cell accumulation behind the blood-brain barrier (BBB). We systematically track CNS-homing immune cells in the peripheral blood of 31 MS patients and 31 matched healthy individuals in an integrated analysis of 497,705 single-cell transcriptomes and 355,433 surface protein profiles from 71 samples. Through spatial RNA sequencing, we localize these cells in post mortem brain tissue of 6 progressive MS patients contrasted against 4 control brains (20 samples, 85,000 spot transcriptomes). We identify a specific pathogenic CD161+/lymphotoxin beta (LTB)+ T cell population that resides in brains of progressive MS patients. Intriguingly, our data suggest that the colonization of the CNS by these T cells may begin earlier in the disease course, as they can be mobilized to the blood by usage of the integrin-blocking antibody natalizumab in relapsing-remitting MS patients. As a consequence, we lay the groundwork for a therapeutic strategy to deplete CNS-homing T cells before they can fuel treatment-resistant progression. This study was supported by funding from the University Medical Center Hamburg-Eppendorf, the Stifterverband für die Deutsche Wissenschaft, the OAK Foundation, Medical Research Council UK, and Wellcome. [Display omitted] Multimodal single-cell profiling of blood and spatial RNA sequencing of brain tissueVLA4 blockage mobilizes CD161+/LTB+ Th17/Tfh cells to the blood early in MSIdentification of these Th17/Tfh as brain-resident cells in progressive MS patientsTargetable surface markers on Th17/Tfh include AQP3, TNFRSF25, ICOS, and VLA4 Multiple sclerosis (MS) is characterized by a rogue immune system that attacks the brain and spinal cord, leading to severe disability in young patients. During early phases of the disease, relapses can still be suppressed by immunomodulatory therapies. Later on, many patients develop a slowly progressive phase that is mostly resistant to available drugs for reasons remaining largely unclear. According to one long-standing theory, the therapeutic resistance might arise due to infiltration and lasting residence of blood immune cells behind the blood-brain barrier, beyond the reach of most therapeutics. In the present st