Transcription factor networks in aged naïve CD4 T cells bias lineage differentiation

Abstract

With reduced thymic activity, the population of naïve T cells in humans is maintained by homeostatic proliferation throughout adult life. In young adults, naïve CD4 T cells have enormous proliferative potential and plasticity to differentiate into different lineages. Here, we explored whether naïve CD4 T‐cell aging is associated with a partial loss of this unbiased multipotency. We find that naïve CD4 T cells from older individuals have developed a propensity to develop into TH9 cells. Two major mechanisms contribute to this predisposition. First, responsiveness to transforming growth factor β (TGFβ) stimulation is enhanced with age due to an upregulation of the TGFβR3 receptor that results in increased expression of the transcription factor PU.1. Secondly, aged naïve CD4 T cells display altered transcription factor profiles in response to T‐cell receptor stimulation, including enhanced expression of BATF and IRF4 and reduced expression of ID3 and BCL6. These transcription factors are involved in TH9 differentiation as well as IL9 transcription suggesting that the aging‐associated changes in the transcription factor profile favor TH9 commitment.

Influence of immune aging on vaccine responses

“…103,104 However, mathematically, an adaptation scenario is favored, where cells adapt to their environment, becoming more fit (ie, acquire a survival or proliferative advantage) with age. 105 It is also more consistent with the loss of stem-like features and reduced plasticity we observe in naive T cells in older individuals, 99,106 and in line with conversion of naive T cells to virtual memory-like cells observed in mice with age. 107,108 Virtual memory cells are a ''naive'' cell population that acquires features of memory T cells without prior antigenic stimulation, driven instead by cytokine-mediated signaling.…”

“…Mechanistically, aged naive CD4 T cells demonstrate a basal shift in transcriptional factor profiles away from a T FH -like signature of BCL6 and ID3. 106 This profile shift also skews naive CD4 subset polarization toward a T H 9 phenotype upon antigenic stimulation in older individuals and may also account for diminished CD4 T FH functionality in response to vaccination with aging. Moreover, an ageassociated increase in miR-21 expression in naive CD4 T cells sustains the activity of several signaling pathways including AKT-the mammalian target of rapamycin and mitogenactivated protein kinase by targeting their negative regulators, thereby promoting the generation of short-lived effector T cells.…”

FOXO1 deficiency impairs proteostasis in aged T cells

“…NS: not significant. (B) GSEA comparing fold transcript differences in young compared with old naïve CD4 + T cells on day 5 after stimulation (accession number: SRA: SRP158502) (19) with that of mouse Foxo1 knockout (KO) unstimulated T cells (46). NES, normalized enrichment score; FDR, false discovery rate.…”

“…Horizontal lines represent mean values; comparison by two-tailed unpaired t test. (G) Transcriptome data from naïve CD4 + T cells from three young and three old healthy individuals stimulated with anti-CD3 and anti-CD28 beads for 5 days (accession number: SRA: SRP158502) (19). Violin plots and boxplots showing the fold gene expression differences of lysosomal genes, comparing the transcriptome of old to young T cells.…”

“…org/gsea/index.jsp) was used to determine the enrichment of gene sets in young (20 to 35 years old) or old (65 to 85 years old) T cells. The datasets describing age-associated differences in activated CD4 + T cells were obtained from the SRA database under accession number SRP158502 (19). Gene sets caused by Foxo1 deficiency were from GSE15037 (46).…”