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.
Gene Expression Omnibus
This work was supported by NIH grants U19AI057266 (R.A.), R01-AI43866-07 (M.H.), NIAID UM1 AI068618 (M.J.Mc.) and NIAID UM1 AI069481 (M.J.Mc.). The authors acknowledge technical support from R. Karaffa and S. Durham for cell sorting.
Extended data figures
This file contains supplementary tables 1-3. Supplementary Table1 - Raw data for deuterium labelling study 1. This table shows the cell division rate, cell growth raye and calculated death rate for each donor in the deuterium labelling study 1. Supplementary Table 2 - Comparing human YFV-specific effector and memory CD8 T cell signatures with mouse effector and memory CD8 T cells. The authors compared the RNA-seq data from YFV-tetramer+ CD8 T cells to published microarray data from mouse CD8 T cells. The authors performed gene set enrichment analysis (GSEA) to determine the degree of overlap of human YFV-specific CD8 T-cells with these mouse CD8 signatures. This table shows the p-value and FDR for each comparison. Supplementary Table 3- Donor Characteristics. The table shows the age, gender and race of the donors who participated in the heavy water labelling studies.