Age-associated alterations in inducible gene transcription in human CD4+ T lymphocytes

TLDR

Age‑associated immune dysregulation creates a pro‑inflammatory state and heightened infection and autoimmune risk, and TCR signaling is impaired in CD4⁺ T cells from older individuals. The study examined how TCR‑inducible gene expression changes in human CD4⁺ T cells during aging. We found that NF‑κB drives a dichotomous response in aged CD4⁺ T cells: most target genes fail to sustain induction, yet a subset—including IL‑1 and IL‑6—remains up‑regulated, and additional widespread transcriptional changes were identified that differ from murine models, providing the first view of age‑associated alterations in TCR‑inducible gene expression.

Abstract

Age associated immune dysregulation results in a pro-inflammatory state and increased susceptibility to infections and autoimmune diseases. Studies show that signaling initiated at the T cell antigen receptor (TCR) is impaired in CD4+ T cells from old compared to young mice. Here we examined TCR-inducible gene expression changes in CD4+ T cells during human aging. We reveal a dichotomy in gene expression mediated by the inducible transcription factor NF-κB. Most NF-κB target genes are not induced in a sustained manner in cells derived from older compared to younger individuals. However, a subset of NF-κB target genes including genes associated with chronic pro-inflammatory state in the elderly, such as interleukin 1 and 6, continue to be up-regulated even in the absence of NF-κB induction. In addition, we identify other widespread changes in gene expression between cells derived from older and younger individuals. Surprisingly, many of the most noteworthy age-associated changes in human CD4+ T cells differ from those seen in murine models. Our studies provide the first view of age-associated alteration of TCR-inducible gene expression in human CD4+ T cells.