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

Abstract

AbstractQuantifying 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, an established fate-mapping system, 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 find strong evidence that cell-age effects dominate host-age effects, and that clones become more quiescent and more persistent the longer they reside within the TCMand TEMpools. This behaviour will lead to an increasingly long-tailed distribution of clone sizes as an individual ages. Therefore, the age structure of CD4+TCMand TEMclones can explain bulk changes in their dynamics and persistence across the lifespan.Author SummaryOur long-term protection against infections depends in part on the maintenance of diverse populations of CD4 memory 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 mouse experiments with mathematical models to show that CD4 memory T cell clones have a complex dynamical structure but become progressively more quiescent with time. Their expected cell lifespan increases as they age, leading to long-tailed survival curves. This dynamic implies that as individuals age, their CD4 memory populations become enriched for older clones that have a fitness advantage over newly generated ones. If these older clones are functionally impaired, this phenomenon may contribute to the waning of immunity in the elderly.