Origin and differentiation of human memory CD8 T cells after vaccination

Abstract

The differentiation of human memory CD8 T cells is not well understood. Here we address this issue using the live yellow fever virus (YFV) vaccine, which induces long-term immunity in humans. We used in vivo deuterium labelling to mark CD8 T cells that proliferated in response to the virus and then assessed cellular turnover and longevity by quantifying deuterium dilution kinetics in YFV-specific CD8 T cells using mass spectrometry. This longitudinal analysis showed that the memory pool originates from CD8 T cells that divided extensively during the first two weeks after infection and is maintained by quiescent cells that divide less than once every year (doubling time of over 450 days). Although these long-lived YFV-specific memory CD8 T cells did not express effector molecules, their epigenetic landscape resembled that of effector CD8 T cells. This open chromatin profile at effector genes was maintained in memory CD8 T cells isolated even a decade after vaccination, indicating that these cells retain an epigenetic fingerprint of their effector history and remain poised to respond rapidly upon re-exposure to the pathogen.

The metabolic spectrum of memory T cells

“…Further links between metabolism and epigenetic regulation of immune cells are beginning to emerge . Recent studies in mice and humans provide evidence that suggests memory T cells arise from effector T‐cell memory precursor pools and can retain an effector like epigenetic signature . This supports the concept that that memory T‐cell differentiation could be linked with epigenetic modifications at specific loci and that these cells are epigenetically poised to respond to secondary stimulation.…”

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

“…Since all these memory T cells share the same phenotypic markers, the lifespan of each of these types of memory cells remained unknown. Recently, Akondy et al reported on a long‐term deuterium‐labeling study to investigate the dynamics of cognate memory T cells in volunteers vaccinated against yellow fever (YF). The investigators were able to determine the deuterium enrichment in a relatively small CD8 + memory tetramer + T‐cell pool specific for this virus.…”

“…A major new finding was that—despite the average lifespan of YV‐specific memory T cells of about 4 months—a large population of labeled memory cells persisted for years after vaccination, and that these persisting cells had a quiescent phenotype with features of stem‐cell‐like and effector‐like memory CD8 + T cells . The latter finding suggests that either CD8 + memory T cells slowly increase their longevity by becoming more quiescent over time, or that the population of antigen‐specific CD8 + memory T cells is kinetically heterogeneous, with the most quiescent subset becoming more predominant over time because they survive longer . Another major new finding was that YV‐specific memory cells had a very long intermitotic interval of 1/0.0015=666 days, that is, longer than their life expectancy.…”

Tissue-Specific Control of Tissue-Resident Memory T Cells

“…4 Although long-lasting debates have been focused on the identity of memory precursors and the differentiation path of memory T cells, 5 recent works have provided solid epigenetic evidence that virus-specific memory T cells transit through an effector stage, not directly derive from naïve cells in both mouse and human. 6,7 …”