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.

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Despite the described clear epigenetic effects of smoking, the effect of smoking on genome-wide gene expression in the blood is obscure. We therefore studied the smoking-induced changes in the gene-expression profile of the peripheral blood. RNA was extracted from the whole blood of 48 individuals with a detailed smoking history (24 never-smokers, 16 smokers, and 8 ex-smokers). Gene-expression profiles were evaluated with RNA sequencing, and results were analyzed separately in 24 men and 24 women. In the male smokers, 13 genes were statistically significantly (false-discovery rate <0.1) differentially expressed; in female smokers, 5 genes. Although most of the differentially expressed genes were different between the male and female smokers, the G-protein-coupled receptor 15 gene (GPR15) was differentially expressed in both male and female smokers compared with never-smokers. Analysis of GPR15 methylation identified significantly greater hypomethylation in smokers compared with that in never-smokers. GPR15 is the chemoattractant receptor that regulates T-cell migration and immunity. Up-regulation of GPR15 could explain to some extent the health hazards of smoking with regard to chronic inflammatory diseases.

BackgroundAgeing affects many components of the immune system, including innate immune cells like monocytes. They are important in the early response to pathogens and for their role to differentiate into macrophages and dendritic cells. Recent studies have revealed significant age-related changes in genomic DNA methylation in peripheral blood mononuclear cells, however information on epigenetic changes in specific leukocyte subsets is still lacking. Here, we aimed to analyse DNA methylation in purified monocyte populations from young and elderly individuals.FindingsWe analysed the methylation changes in monocytes purified from young and elderly individuals using the HumanMethylation450 BeadChip array. Interestingly, we found that among 26 differentially methylated CpG sites, the majority of sites were hypomethylated in elderly individuals. The most hypomethylated CpG sites were located in neuropilin 1 (NRP1; cg24892069) and neurexin 2 (NRXN2; cg27209729) genes, and upstream of miR-29b-2 gene (cg10501210). The age-related hypomethylation of these three sites was confirmed in a separate group of young and elderly individuals.ConclusionsWe identified significant age-related hypomethylation in human purified monocytes at CpG sites within the regions of NRP1, NRXN2 and miR-29b-2 genes.

Epigenetic changes at specific genetic loci and the activation of transcriptional repressor FOXP3 are needed to establish and maintain the regulatory T cell (Treg) lineage. Here we studied the DNA methylation profiles in CD4+ CD25+ Tregs and CD4+ CD25- conventional T cells (Tconvs) from healthy individuals and identified a wide range of differentially methylated CpG sites (DMPs). Overall, Tregs had more hypomethylated DMPs and contained more CpG sites, which on the cell population level were less defined in their methylation status. We identified top hypomethylated CpGs in Tregs close to CENPM, IKZF2, and LYST and hypermethylated sites at the THEMIS, SCML4, and ADD3 genes. Among others, DMPs were enriched for the transcriptional repressor Kaiso binding motifs. Interestingly, in Tregs we found hypomethylation and increased expression of the TSHR gene, which is a risk gene for Graves' disease (GD). However, subsequent DNA methylation profiling in healthy individuals and GD patients revealed only 19 DMPs and no change at the TSHR locus, indicating that Tregs in GD patients share a similar methylation pattern with healthy controls. Together, we show Treg-specific hypomethylation and expression of the TSHR gene, prompting additional scenarios to explain the genetic link and role of anti-TSHR autoantibodies in GD.