Work

Cytomegalovirus Drives the Development of Cytotoxic CD4 + T Cells in Patients With Multiple Sclerosis

Year: 2026

Type: article

Abstract: BACKGROUND AND OBJECTIVES: cytotoxic T lymphocytes (CD4 CTL). The mechanisms underlying CD4 CTL development remain elusive, although antigenic triggers and the local microenvironment are thought to influence their phenotype. In this study, it was investigated if CD4 CTL induced under different circumstances exhibit phenotypic differences. METHODS: Using single cell multiomics, we analyzed CD4 CTL from healthy cytomegalovirus (CMV)-seropositive donors, patients with CMV-seronegative relapsing-remitting multiple sclerosis (RR-MS) (autoimmune trigger), and patients with CMV-seropositive RR-MS (combination of viral and autoimmune trigger). RESULTS: Our findings reveal that the heterogeneous pool of CD4 CTL encompasses distinct subsets with divergent expression of proinflammatory, cytotoxic, and migratory markers. Moreover, we identified a pathogenic CD4 CTL subset coexpressing the MS-associated transcription factor eomesodermin (EOMES) and the migratory receptor class I-restricted T-cell-associated molecule, which accumulates in MS lesions and demonstrates resistance to natalizumab treatment. DISCUSSION: T cells, as these cells were markedly enriched in CMV-seropositive individuals. This comprehensive phenotypic atlas of CD4 CTL advances our understanding of their development and highlights potential targets for diagnosing, treating, and preventing MS progression.

Source: Neurology Neuroimmunology & Neuroinflammation

DOI: 10.1212/nxi.0000000000200561