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

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.