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

Abstract

SummaryAdaptive 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 (TSCM) cells, multipotent progenitors that can both self-renew and replenish more differentiated subsets of memory T cells. In theory, antigen specificity within the TSCM 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 TSCM cells in vivo using stable isotope labeling with heavy water. The data indicate that TSCM cells in both young and elderly subjects are maintained by ongoing proliferation. In line with this finding, TSCM cells displayed limited telomere length erosion coupled with high expression levels of active telomerase and Ki67. Collectively, these observations show that TSCM cells exist in a state of perpetual flux throughout the human lifespan.

Origin and differentiation of human memory CD8 T cells after vaccination

“…Previous deuterium labelling studies in humans 12,14–16 , investigating the turnover rate of bulk memory CD8 T cell subsets, have reported higher rates of cell proliferation than those we have found when tracking YFV-specific CD8 T cells (Figs 1, 2). In these earlier studies, the specificity and antigenic history of the T cells being analysed was not known.…”

Current best estimates for the average lifespans of mouse and human leukocytes: reviewing two decades of deuterium‐labeling experiments

“…It is perhaps not surprising that a 9‐week labeling protocol cannot distinguish between these very long lifespans, but the finding that naive T cells still contained measurable levels of deuterium 3 to 4 years after stop of labeling convincingly shows that naive T cells in humans are very long‐lived . Actually, the very low rates of accrual and loss of deuterium in the naive T‐cell populations described in Table are quite surprising in the light of the recently described subpopulation of stem cell memory T cells (T SCM ), which share the same naive T‐cell markers and were found to be very short‐lived …”

“…This difference was probably caused by a relatively high percentage of CD95 + T cells in the CD8 + T‐cell pools of aged volunteers. Although we classified these cells as naive based on the expression of CD27 and the lack of expression of CD45RO, they may have included highly dynamic cells such as stem‐cell memory (T SCM ) cells . Indeed, based on their high Ki67 expression levels, these CD95 + T cells turned out to divide much more frequently than their CD95 − counterparts .…”

“…Recently, Ahmed et al performed a 7‐week deuterium‐labeling study, sorting CD4 + and CD8 + human T cells into CD27 bright CD45RO − CCR7 + CD95 − naive T cells, CD27 bright CD45RO − CCR7 + CD95 + T SCM T cells, CD45RA + CD45RO + transitional memory (T TM ) T cells, and CD45RA − memory CD4 + and CD8 + T cells. The data were fitted with various alternative models for the differentiation of these subsets (similar to Equations ‐ in Box 1).…”

Single-cell technologies for profiling T cells to enable monitoring of immunotherapies

“…T cells are capable of many different functions including cytotoxicity, cytokine secretion, proliferation, and migration, which are determined by multiple cues from intrinsic properties of T cells and its environmental factors. The relative importance of these functions in defining clinical benefit is only partially understood and confounded by the differentiation status of the T cell (naïve, stem-cell-like central memory, central memory, effector memory and effector) [32,33], or by their functional status (polyfunctional, anergic, or exhausted). It is thus apparent that the availability of methods that can map all of these properties onto the same T cell will advance our understanding of the efficacy of immunotherapeutic treatments.…”