Age-related profiling of DNA methylation in CD8+ T cells reveals changes in immune response and transcriptional regulator genes

Abstract

Human ageing affects the immune system resulting in an overall decline in immunocompetence. Although all immune cells are affected during aging, the functional capacity of T cells is most influenced and is linked to decreased responsiveness to infections and impaired differentiation. We studied age-related changes in DNA methylation and gene expression in CD4+ and CD8+ T cells from younger and older individuals. We observed marked difference between T cell subsets, with increased number of methylation changes and higher methylome variation in CD8+ T cells with age. The majority of age-related hypermethylated sites were located at CpG islands of silent genes and enriched for repressive histone marks. Specifically, in CD8+ T cell subset we identified strong inverse correlation between methylation and expression levels in genes associated with T cell mediated immune response (LGALS1, IFNG, CCL5, GZMH, CCR7, CD27 and CD248) and differentiation (SATB1, TCF7, BCL11B and RUNX3). Our results thus suggest the link between age-related epigenetic changes and impaired T cell function.

Mechanisms Underlying T Cell Immunosenescence: Aging and Cytomegalovirus Infection

“…It is well-known that genome-wide decreases in the methylation of repetitive elements (particularly Alu sequences) and gene coding regions occur during aging (Bollati et al, 2009; Heyn et al, 2012; Salpea et al, 2012). These age-dependent DNA methylation changes also occur in immune-specific genes that contribute to T cell senescence (Shanley et al, 2009; Fernández-Morera et al, 2010; Hongdong et al, 2015; Tserel et al, 2015). …”

Tissue aging: the integration of collective and variant responses of cells to entropic forces over time

“…Second, epigenetic shifts are directional DNA methylation states at specific sites that seem to be stereotyped and age-specific across individuals. For example, methylation and chromatin accessibility of the genome organizer SATB1 is negatively correlated with age in T-cells[41], and genes used in autophagy are hypermethylated in aging macrophages[43]. Currently, the directness of the relationship between epigenetic marks and transcriptional outputs is still unclear.…”

Nutrients and the microenvironment to feed a T cell army

“…A study of CD8+ T lymphocytes from geriatric and young patients showed methylation status of T cells was significantly more variable in geriatric CD8+ T cells and this correlated with decreased immune function. Several genes important in CD8+ T cell differentiation and immune response, such as IFNy and CCL5, had decreased methylation which correlated with higher transcription levels[85]. These studies were confounded, however, by decreased naïve T cells and increased memory T cells in the older population, which could skew the methylation status data.…”