Aging substantially impairs development and progression of autoimmune and neurodegenerative diseases. In MS, an age-related decline in disease activity and a decreased efficacy of disease-modifying treatments have been reported and linked to immunosenescence. 

Using multiparameter flow cytometry, we performed comprehensive immunophenotyping of PB and CSF in age- and sex-matched patients with relapsing-remitting MS (RRMS) and primary progressive MS (PPMS) compared to respective controls.

During aging, we identified significant changes in the peripheral CD8 T cell compartment of MS patients and healthy donors (HD). There was an age-related decline in the expression of the immunoregulatory molecules KLRG1, LAG3, and CTLA-4 on memory CD8 T cells in HD. This age-dependent decrease was completely abolished in MS patients, as young MS patients (≤ 50 years) already demonstrated similar expression levels of these molecules as old HD (> 50 years). Moreover, we did not observe an age-dependent increase in the expression of the costimulatory molecule CD226 (DNAM-1) on memory CD8 T cells in MS patients, which was present in HD. Remarkably, we identified a potential correlation between premature immunosenescence and disease activity, as the expression levels of CD226 on memory CD8 T cells correlated positively with disability scores in young MS patients. In an independent cohort, we evaluated an age-related decline in major immune cell subsets in the CSF of PPMS patients, suggesting a differential age-related regulation of inflammation in the CSF.

Our data show that aging in MS is associated to an imbalance between costimulatory and immunoregulatory signals on memory CD8 T cells favoring a pattern of premature immunosenescence in young MS patients with potential implications for disease activity.