The Role of T Cells in Multiple Sclerosis: Molecular Mechanisms, Drivers, and Therapeutic Targets

Multiple sclerosis is a chronic immune-mediated disease of the central nervous system, marked by demyelination, axonal damage, and progressive neurological decline. T lymphocytes-particularly CD4⁺, T helper (Th)1 and Th17 cells, as well as cytotoxic CD8⁺ cells-play a pivotal role in initiating and sustaining central nervous system inflammation. Acute inflammation is driven by peripheral immune activation, while progressive disease reflects compartmentalized, smouldering inflammation within the central nervous system, dominated by CD8⁺ T cells and microglia. A relative deficiency or dysfunction of regulatory T cells contributes to immune tolerance loss and ongoing neurodegeneration. Although T lymphocytes play a central role, the pathogenesis of multiple sclerosis involves a broader cellular network, including antigen-presenting cells, B lymphocytes, microglia, and astrocytes. While recent therapeutic strategies have increasingly focused on B lymphocytes, most disease-modifying therapies-and many emerging ones-exert at least partial effects by modulating T cell-mediated mechanisms. These insights underpin current T cell-targeted therapies and highlight unmet needs in multiple sclerosis.