Human T SCM cell dynamics in vivo are compatible with long-lived immunological memory and stemness

Abstract

Adaptive immunity relies on the generation and maintenance of memory T cells to provide protection against repeated antigen exposure. It has been hypothesised that a self-renewing population of T cells, named stem cell–like memory T (T SCM ) cells, are responsible for maintaining memory. However, it is not clear if the dynamics of T SCM cells in vivo are compatible with this hypothesis. To address this issue, we investigated the dynamics of T SCM cells under physiological conditions in humans in vivo using a multidisciplinary approach that combines mathematical modelling, stable isotope labelling, telomere length analysis, and cross-sectional data from vaccine recipients. We show that, unexpectedly, the average longevity of a T SCM clone is very short (half-life < 1 year, degree of self-renewal = 430 days): far too short to constitute a stem cell population. However, we also find that the T SCM population is comprised of at least 2 kinetically distinct subpopulations that turn over at different rates. Whilst one subpopulation is rapidly replaced (half-life = 5 months) and explains the rapid average turnover of the bulk T SCM population, the half-life of the other T SCM subpopulation is approximately 9 years, consistent with the longevity of the recall response. We also show that this latter population exhibited a high degree of self-renewal, with a cell residing without dying or differentiating for 15% of our lifetime. Finally, although small, the population was not subject to excessive stochasticity. We conclude that the majority of T SCM cells are not stem cell–like but that there is a subpopulation of T SCM cells whose dynamics are compatible with their putative role in the maintenance of T cell memory.