Blood cytotoxic natural killer-like CD8 + CD94+ T cells migrate to the brain and predict multiple sclerosis severity

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.

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Publication Details

Journal
Brain
Published
2026-06-30
DOI
https://doi.org/10.1093/brain/awag227
Primary Topic
Neuroinflammation and Neurodegeneration Mechanisms
Type
article
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article

Blood cytotoxic natural killer-like CD8 + CD94+ T cells migrate to the brain and predict multiple sclerosis severity

E Le Page, Amédée Renand, Céline Monvoisin, Mélinda Moyon et al.
Brain
Neuroinflammation and Neurodegeneration Mechanisms
article

Blood cytotoxic natural killer-like CD8 + CD94+ T cells migrate to the brain and predict multiple sclerosis severity

E Le Page, Amédée Renand, Céline Monvoisin, Mélinda Moyon, Karin Tarte, Aurélie Ruet, Emilie Dugast, Pierre‐Antoine Gourraud, Romain Casey, Jérémie Poschmann, D. Laplaud, Léo Boussamet, Marylène Jacq-Foucher, Laureline Berthelot, Jean-Benoît Le Luduec, Hanane Agherbi, Serge Nataf, Clara Ballerini, Cynthia Fourgeux, Victor Gourain, Fabienne Le Frère, Roberta Amoriello, Alexandra Garcia, Sandrine Wiertlewski, Catarina Raposo, Pierre Labauge, Amandine Loret, Sandra Vukusic, Guillaume Mathey, Isabel Vogel, Laure Michel, Arnaud Nicot, Sita Shah, Eric Thouvenot
article en

Abstract

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.

Brain
Université Claude Bernard Lyon 1 (FR), Roche (Switzerland) (CH), Centre National de la Recherche Scientifique (FR), Memorial Sloan Kettering Cancer Center (US), Université de Bordeaux (FR), Inserm (FR), Lyon College (US), Multiple Sclerosis Foundation (US), Centre Hospitalier Universitaire de Bordeaux (FR), Centre Hospitalier Universitaire de Nantes (FR), Centre Hospitalier Universitaire de Montpellier (FR), Centre de Recherche en Neurosciences de Lyon (FR), Centre Hospitalier Régional et Universitaire de Nancy (FR), Hospices Civils de Lyon (FR), Observatoire Français de la Sclérose en Plaques (FR), Centre Hospitalier Universitaire de Nîmes (FR), Institut de Transplantation Urologie en Nephrologie (FR), CIC Rennes (FR), Hôpital Pontchaillou (FR), Neurocentre Magendie (FR), Centre d'Investigation Clinique de Nantes (FR), Institut Cellule Souche et Cerveau (FR), Institut de Génomique Fonctionnelle (FR), Interdisciplinarité en Santé Publique Interventions et Instruments de mesure complexes – Région Est (FR), University of Florence (IT), Université de Rennes (FR), Université de Lorraine (FR), Nantes Université (FR)
Good health and well-being
Openalex Percentile: Top 9%
Neuroinflammation and Neurodegeneration Mechanisms
DOISourceOpenAlex
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