Blood cytotoxic natural killer-like CD8 + CD94+ T cells migrate to the brain and predict multiple sclerosis severity
Emilie Dugast, Sita Shah, Isabel Vogel, Amandine Loret, Céline Monvoisin, Alexandra Garcia, Cynthia Fourgeux, Victor Gourain, Léo Boussamet, Roberta Amoriello, Jean-Benoît Le Luduec, Serge Nataf, Marylène Jacq-Foucher, Melinda Moyon, Fabienne Le Frère, Sandrine Wiertlewski, Clara Ballerini, Karin Tarte, Eric Thouvenot, Hanane Agherbi, Romain Casey, Sandra Vukusic, Aurélie Ruet, Emmanuelle Le Page, Pierre Labauge, Guillaume Mathey, Catarina Raposo, Jérémie Poschmann, Amedée Renand, Arnaud Nicot, Laure Michel, Pierre-Antoine Gourraud, Laureline Berthelot, David-Axel LaplaudAbstract
Memory CD8+ T cells are central to multiple sclerosis (MS) and undergo clonal expansion, but disease-associated states remain incompletely defined.
By single-cell profiling of circulating memory CD8+ T cells from patients with relapsing–remitting MS, healthy volunteers, and neuroinflammatory controls, we identified an MS-associated cytotoxic subset with NK-like features. These cells increase around relapse activity and belong to an oligoclonal reservoir. In an independent cohort sampled at the first clinical event, an elevated frequency of NK-like CD8+ T cells predicted an aggressive MS course two years later and was associated with a migratory/inflammatory program. Bulk and single-cell RNA-seq confirmed the NK-like transcriptional signature, and functional assays demonstrated TCR-independent cytotoxicity. Immunostaining and spatial transcriptomics revealed enrichment of these cells in MS lesions and a spatial association with macrophages/microglia.
Together, our results identify a cytotoxic NK-like CD8+ T-cell subset that links peripheral inflammation to CNS lesions and may serve as an early biomarker of MS severity.