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.
Highlights
Ageing progressively affects the activity of the immune system
Less than 2% of the age-related methylation sites in CD4+ and CD8+ T cells could be detected in peripheral blood leukocytes (PBL), and majority of them were hypermethylated in older population
We here report age-related methylation changes that were identified in CD4+ and CD8+ T cells by analyzing more than 400,000 CpG sites from a total of 100 individuals
Summary
Ageing progressively affects the activity of the immune system. The age-related decline in immune responses, termed immunosenescence, is prominent in the adaptive immune system, where T cells appear to be most affected during ageing[1,2]. The concept of an immune risk profile, associated with higher mortality rates, has been proposed This is composed of depleted naïve T cell numbers, an inverted CD8+ /CD4+ T cell ratio, low responses to mitogen stimulation, increased population of anergic terminally differentiated CD8+ T cells and increased pro-inflammatory cytokine expression[11]. Even if normalization tools are applied[27], the use of purified cell subsets is superior to the identification of methylome changes and their correlation to cell-type specific functions In light of these considerations we focused on sorted CD4+ and CD8+ T cells and aimed to identify whether the DNA methylation changes are involved in development of age-related decrease of T cell responsiveness. Our genome-wide analyses indicate for the first time in CD8+ T cell subset a strong age-related correlation of DNA methylation and the expression of genes having functional role in controlling T cell immune responses and their differentiation
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