Search

Summary Tobacco smoke exposure contributes to the global burden of communicable and chronic diseases. To identify the immune cells affected by smoking, we use single-cell RNA sequencing on peripheral blood from smokers and nonsmokers. Transcriptomes reveal a subpopulation of FCGR3A (CD16)-expressing natural killer (NK)-like CD8 T lymphocytes that increase in smokers. Mass cytometry confirms elevated CD16+ CD8 T cells in smokers. Inferred as highly differentiated by pseudotime analysis, NK-like CD8 T cells express markers that are characteristic of effector memory re-expressing CD45RA T (TEMRA) cells. Indicative of immune aging, smokers’ CD8 T cells are biased toward differentiated cells, and smokers have fewer naive cells than nonsmokers. DNA methylation-based models show that smoking dose is associated with accelerated aging and decreased telomere length, a biomarker of T cell senescence. Immune aging accompanies T cell senescence, which can ultimately lead to impaired immune function. This suggests a role for smoking-induced, senescence-associated immune dysregulation in smoking-mediated pathologies., Graphical Abstract, Highlights Smoking shifts the composition of CD8 T cells from naive to differentiated states NK-like CD16+ CD8 TEMRA cells are elevated in smokers and express GZMB and PRF1 DNA methylation links smoking dose with age acceleration and shortened telomeres CD8 T, CD4 T, NKT, NK, and monocytes express senescence-linked genes in smokers, Smoking increases the risk of inflammatory diseases and decreases immunity. Martos et al. characterize immune cells and find that smoking reduces naive and increases late-stage CD8 T cells. They show that smoking dose is associated with age acceleration and shortened telomeres. These changes are consistent with immune aging and senescence.