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Thymic involution is a key factor in human immune aging, leading to reduced thymic output and a decline in recent thymic emigrant (RTE) naive T cells in circulation. Currently, the precise definition of human RTEs and their corresponding cell surface markers lacks clarity. Analysis of single-cell RNA-seq/ATAC-seq data distinguished RTEs by the expression of SOX4, IKZF2, and TOX and CD38 protein, whereby surface CD38hi expression universally identified CD8+ and CD4+ RTEs. We further determined the dynamics of RTEs and mature cells in a cohort of 158 individuals, including age-associated transcriptional reprogramming and shifts in cytokine production. Spectral cytometry profiling revealed two axes of aging common to naive CD8+ and CD4+ T cells: (1) a decrease in CD38++ cells (RTEs) and (2) an increase in CXCR3hi cells. Identification of RTEs enables direct assessment of thymic health. Furthermore, resolving the dynamics of naive T cell remodeling yields insight into vaccination and infection responsiveness throughout aging. [Display omitted] • Human RTEs are epigenetically and transcriptionally defined by SOX4, IKZF2, and TOX • Both CD8+ and CD4+ RTEs are characterized by high surface expression of CD38 • CD38 expression is a reliable RTE marker also under chronic and acute inflammation • Naive T cells show an age-related decline in CD38++ RTEs and an increase in CXCR3hi cells Identifying human T cells that have recently emigrated from the thymus remains problematic. Here, Bohacova et al. categorize recent thymic emigrants with high CD38 expression as their universal surface marker. Additionally, they explore the transcriptional and epigenetic landscape of naive CD8+ and CD4+ T cells, revealing shared axes of aging. [ABSTRACT FROM AUTHOR]

Extensive, large-scale single-cell profiling of healthy human blood at different ages is one of the critical pending tasks required to establish a framework for the systematic understanding of human aging. Here, using single-cell RNA/T cell receptor (TCR)/BCR-seq with protein feature barcoding, we profiled 317 samples from 166 healthy individuals aged 25–85 years old. From this, we generated a dataset from ∼2 million cells that described 55 subpopulations of blood immune cells. Twelve subpopulations changed with age, including the accumulation of GZMK +CD8+ T cells and HLA-DR +CD4+ T cells. In contrast to other T cell memory subsets, transcriptionally distinct NKG2C + GZMB − CD8+ T cells counterintuitively decreased with age. Furthermore, we found a concerted age-associated increase in type 2/interleukin (IL)4-expressing memory subpopulations across CD4+ and CD8+ T cell compartments (CCR4 +CD8+ Tcm and Th2 CD4+ Tmem), suggesting a systematic functional shift in immune homeostasis with age. Our work provides novel insights into healthy human aging and a comprehensive annotated resource. [Display omitted] • Clinical and scRNA-seq data of 2 million PBMCs from 166 people aged 25–85 years old • Type 2 memory CD4+ and CD8+ T cells increase with age and can produce more IL-4 • NKG2C+GZMB–XCL1+ defines a unique memory CD8+ T cell subset that decreases with age • HLA-DR+ CD4+ memory T cells and GZMK+ CD8+ T cells accumulate with age Terekhova et al. perform single-cell RNA sequencing on >300 samples between 25 and 85 years to comprehensively profile immune changes throughout aging. This resource revealed 12 subpopulations that change with age, including increased type 2 memory CD4+ and CD8+ T cells and decreased NKG2C+GZMB−CD8+ memory population. [ABSTRACT FROM AUTHOR]