Single-cell atlas of healthy human blood unveils age-related loss of NKG2C+GZMB−CD8+ memory T cells and accumulation of type 2 memory T cells.

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]