RNA-sequencing of FACS-sorted MCAM+CCR6+ Th17 cells derived from treatment-naive MS patients and MS patients with long-term Natalizumab treatment. Th17 Pathogenicity Natalizumab

After natalizumab (NAT) cessation, some multiple sclerosis (MS) patients may experience a severe disease rebound. Rebound pathophysiology is still unclear; however, it has been linked to interleukin-17-producing T-helper (Th17) cells. We here demonstrate that during NAT treatment, MCAM+CCR6+Th17 cells gradually acquire a pathogenic profile, including proinflammatory cytokine production, pathogenic transcriptional signatures, and enhanced brain endothelial barrier impairment and oligodendrocyte damage. This was accompanied by an increase in Th17 cell frequencies in the cerebrospinal fluid of NAT patients. Notably, transcriptional signatures of Th17 cells derived from NAT patients, who later developed a disease rebound upon treatment cessation, additionally displayed enhanced IFNγ-signaling and migratory properties. Accordingly, increased brain infiltration was illustrated in vivo in a humanized mouse model and in brain histology from a rebound patient. In conclusion, PB accumulated MCAM+CCR6+Th17 cells might be implicated in disease rebound pathophysiology, thus monitoring changes in Th17 cell pathogenicity in patients before/during NAT treatment cessation might enable rebound risk prediction in the future.