Aging promotes reorganization of the CD4 T-cell landscape toward extreme phenotypes implicated in age-related diseases

Aging can be considered as a gradual decline in repair processes resulting in accumulating tissue damage and dysfunction that impact life quality and longevity. As life expectancy is continuously on the rise, it becomes essential to elucidate mechanisms of repair failure so that age-related diseases can be better predicted, monitored, prevented and/or treated. Age-associated changes in the functionality of CD4 T cells have been linked to declined immunity and chronic inflammation. However, a detailed characterization of CD4 T-cell phenotypes, which may explain these dysregulated functional properties, is lacking. Here, we used single-cell RNA sequencing and multidimensional protein analyses to profile thousands of CD4 T cells obtained from young and old mice. We found that the landscape of CD4 T-cell subsets is markedly different between young and old mice, such that three cell subsets, including exhausted, cytotoxic, and activated regulatory (aTregs) cells, appear rarely in young mice and gradually accumulate with age. Most unexpected were the cytotoxic CD4 T cells and aTregs exhibiting extreme pro- and anti-inflammatory phenotypes, respectively. These findings provide a comprehensive view of the dynamic reorganization of the CD4 T-cell milieu with age and illuminate dominant cell subsets associated with declined immunity and chronic inflammation, suggesting new therapeutic avenues for age-related diseases.