Exercise reshapes cellular immunity toward anti-inflammation and diminishes CCR4 levels on LFA-1α ^high CD4 ⁺ T cells in multiple sclerosis

Multiple sclerosis (MS) represents a multifaceted neuroinflammatory disease for which regular exercise is now recommended by many healthcare institutions. Although preclinical studies indicate robust immunomodulatory effects of exercise, evidence from human studies is lacking. In this randomized controlled trial, persons with MS (pwMS) were assigned to three months of high-intensity interval training or a passive control condition, with outcomes assessed at baseline, after intervention, and a four- week follow-up. Additionally, a healthy matched control group was included. Besides exercise-induced sustained increases in physical fitness, systemic inflammation was diminished and the T _reg -to-T _H 17.1 ratio improved after exercise. Untargeted proteomic analysis of peripheral blood mononuclear cells covering >7000 proteins revealed an exercise-induced decrease in proteins implicated in inflammatory diseases (i.e., MTHFD2). This was supported by inferred transcription factor activity analysis, which indicated enhanced polarization of immune cells toward anti-inflammatory phenotypes at follow-up. Using flow cytometry, we identified an LFA-1α ^high CD4 ⁺ T-cell subset that was associated with disease biomarkers and exhibited increased CCR4 expression compared to healthy matched subjects which was reduced after exercise. Our findings significantly expand knowledge of how exercise training exerts immediate and sustained immunomodulatory effects in pwMS and thereby strengthens the mechanistic rationale for exercise recommendations made by healthcare professionals.