Abstract
Chronic antigen exposure drives CD4⁺ T cell senescence, yet how autoimmunity and persistent viral infections differentially shape T cell differentiation and function remains unclear. Using cytomegalovirus (CMV) and rheumatoid arthritis (RA) as models of chronic immune activation, we performed high-dimensional mass cytometry and functional assays to define their impact on CD4⁺ T cells. In CMV-seropositive individuals, CD27(-)CD28(-) CD4⁺ T cells were abundant and exhibited a predominantly cytotoxic, nonproliferative phenotype. Only a minor fraction was CMV-reactive, suggesting that bystander-driven differentiation contributes to this subset. In the absence of CMV, senescent CD4⁺ T cells were infrequent and phenotypically distinct, though they still exhibited low proliferative capacity. EBV and HSV did not independently increase CD27(-)CD28(-) CD4⁺ T cell frequency. Similarly, RA had little effect on their abundance but instead tuned the functional quality of senescent cells. In CMV-seropositive RA patients, senescent CD4⁺ T cells produced less pro-inflammatory cytokines and showed impaired cytotoxic degranulation. Central memory CD4⁺ and CD27(-)CD28(-) CD8⁺ T cell functions were preserved, with no evidence for CMV reactivation, suggesting maintained viral control by unaffected T cell responses. These findings highlight distinct, nonredundant effects of CMV and RA on CD4⁺ T cell senescence and reveal RA-specific functional defects in senescent CD4⁺ T cells.