The chromatin accessibility signature of human immune aging stems from CD8+ T cells

TLDR

Aging is associated with immune deficiencies and heightened systemic inflammation. The study aimed to uncover the regulatory programs underlying these changes by profiling chromatin accessibility and transcriptomes across PBMCs and purified monocytes, B cells, and T cells to identify biomarkers and mechanistic insights into aging‑associated immunodeficiency. Using systems immunology, the authors profiled chromatin accessibility and transcriptomes in PBMCs and purified monocytes, B cells, and T cells. Analysis of 77 young and elderly donors revealed a robust aging signature in PBMCs marked by widespread chromatin closing at promoters and enhancers of T‑cell signaling genes, stochastic opening at quiescent sites, loss of NF‑κB and STAT binding in memory CD8⁺ T cells, and silencing of IL7R and IL‑7 pathway genes as potential biomarkers.

Abstract

Aging is linked to deficiencies in immune responses and increased systemic inflammation. To unravel the regulatory programs behind these changes, we applied systems immunology approaches and profiled chromatin accessibility and the transcriptome in PBMCs and purified monocytes, B cells, and T cells. Analysis of samples from 77 young and elderly donors revealed a novel and robust aging signature in PBMCs, with simultaneous systematic chromatin closing at promoters and enhancers associated with T cell signaling and a potentially stochastic chromatin opening mostly found at quiescent and repressed sites. Combined analyses of chromatin accessibility and the transcriptome uncovered immune molecules activated/inactivated with aging and identified the silencing of the IL7R gene and the IL-7 signaling pathway genes as potential biomarkers. This signature is borne by memory CD8+ T cells, which exhibited an aging-related loss in binding of NF-κB and STAT factors. Thus, our study provides a unique and comprehensive approach to identifying candidate biomarkers and provides mechanistic insights into aging-associated immunodeficiency.