Human Stem Cell-like Memory T Cells Are Maintained in a State of Dynamic Flux

Adaptive immunity requires the generation of memory T cells from naive precursors selected in the thymus. The key intermediaries in this process are stem cell-like memory T (T_SCM) cells, multipotent progenitors that can both self-renew and replenish more differentiated subsets of memory T cells. In theory, antigen specificity within the T_SCM pool may be imprinted statically as a function of largely dormant cells and/or retained dynamically by more transitory subpopulations. To explore the origins of immunological memory, we measured the turnover of T_SCM cells in vivo using stable isotope labeling with heavy water. The data indicate that T_SCM cells in both young and elderly subjects are maintained by ongoing proliferation. In line with this finding, T_SCM cells displayed limited telomere length erosion coupled with high expression levels of active telomerase and Ki67. Collectively, these observations show that T_SCM cells exist in a state of perpetual flux throughout the human lifespan.