Cell age, not chronological age, governs the dynamics and longevity of circulating CD4+ memory T cells

Quantifying the kinetics with which memory T cell populations are generated and maintained is essential for identifying the determinants of the duration of immunity. The quality and persistence of circulating CD4+ effector memory (TEM) and central memory (TCM) T cells in mice appear to shift with age, but it is unclear whether these changes are driven by the aging host environment, by cell age effects, or both. Here we address these issues by combining DNA labelling methods, established fate-mapping systems, a novel reporter mouse strain, and mathematical models. Together, these allow us to quantify the dynamics of both young and established circulating memory CD4+ T cell subsets, within both young and old mice. We show that that these cells and their descendents become more persistent the longer they reside within the TCM and TEM pools. This behaviour may limit memory CD4 T cell diversity by skewing TCR repertoires towards clones generated early in life, but may also compensate for functional defects in new memory cells generated in old age. Author summaryOur long-term protection against infections depends in part on the maintenance of diverse populations of memory CD4 T cells, which are made in response to the initial exposure to the pathogen or a vaccine. These cells are not long-lived, but instead are maintained dynamically at a clonal level through loss and division. Understanding how immune memory persists therefore requires measuring these rates of these processes, and how they might change with age. Here we combine experiments in mice with mathematical models to show that memory CD4 T cells exhibit complex dynamics but increase their capacity to survive as they age. This dynamic implies that as individuals age, their memory CD4 T cell populations become enriched for older clones. This established memory may compensate for functional defects in new T cell responses generated later in life.