# Divergent Effects of Cytomegalovirus and Rheumatoid Arthritis on Senescent CD4+ T Cells

## TL;DR

This study shows how chronic infections like CMV and autoimmune diseases like RA differently affect the aging of CD4+ T cells, with CMV causing more cytotoxic cells and RA altering their function.

## Contribution

The paper reveals distinct effects of CMV and RA on CD4+ T cell senescence, highlighting differences in expansion and functional quality.

## Key findings

- CMV drives expansion of cytotoxic CD27−CD28− CD4⁺ T cells with low proliferative capacity.
- RA modulates the functional quality of senescent CD4⁺ T cells, reducing pro-inflammatory cytokine production and cytotoxic degranulation.
- EBV and HSV do not independently increase CD27−CD28− CD4⁺ T cell frequency.

## 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.

How chronic immune stimulations differentially shape CD4⁺ T cell senescence remains unclear. Using high‐dimensional mass cytometry and functional profiling, we show that cytomegalovirus (CMV) drives expansion of cytotoxic CD27−CD28− CD4⁺ T cells, whereas rheumatoid arthritis (RA) exerts nonredundant effects by modulating their effector capacity.