Age-Associated DNA Methylation Changes in Naive CD4 ⁺ T Cells Suggest an Evolving Autoimmune Epigenotype in Aging T Cells

Abstract

Aim:We sought to define age-associated DNA methylation changes in naive CD4 + T cells. Materials & methods: Naive CD4 + T cells were collected from 74 healthy individuals (age 19-66 years), and age-related DNA methylation changes were characterized. Results: We identified 11,431 age-associated CpG sites, 57% of which were hypermethylated with age. Hypermethylated sites were enriched in CpG islands and repressive transcription factor binding sites, while hypomethylated sites showed T cell specific enrichment in active enhancers marked by H3K27ac and H3K4me1. Our data emphasize cancer-related DNA methylation changes with age, and also reveal age-associated hypomethylation in immune-related pathways, such as T cell receptor signaling, FCγR-mediated phagocytosis, apoptosis and the mammalian target of rapamycin signaling pathway. The MAPK signaling pathway was hypermethylated with age, consistent with a defective MAPK signaling in aging T cells. Conclusion: Ageassociated DNA methylation changes may alter regulatory mechanisms and signaling pathways that predispose to autoimmunity.

Detailed analysis of adenosine A2a receptor (ADORA2A) and CD73 (5′-nucleotidase, ecto,NT5E) methylation and gene expression in head and neck squamous cell carcinoma patients

“…33,34 Such age-associated methylation changes frequently affect genes involved in immune processes which are predominantly demethylated with increasing age. [35][36][37] Figure 5. Association of ADORA2A methylation and A2aR mRNA expression with survival.…”

Immune senescence, epigenetics and autoimmunity

“…However, it is important to note the role of epigenetics as a mechanistic link between immunosenescence and autoimmunity. A recent study by Dozmorov et al reports the age-associated DNA methylation changes in naïve CD4+ T cells from healthy individuals [98]. The authors identified 11,431 age-associated CpG sites, over half of which were hypermethylated with age.…”

Review article: next‐generation transformative advances in the pathogenesis and management of autoimmune hepatitis

“…Epigenetic modifications of gene activity are mechanisms whereby environmental cues can influence genetic code and in turn affect cellular response . Pollutants, pharmaceuticals, infectious agents, diet and ageing have been implicated as environmental factors that can induce epigenetic changes . These changes may in turn influence the propensity for autoimmunity .…”

“…Tobacco smoke, aerosolised particles, heavy metals and toxins (trichloroethylene) are environmental factors that may alter the DNA methylation of immune regulatory genes . Hydralazine and procainamide are drugs that inhibit DNA methyltransferase activity, and old age has been associated with genomic instability and hypo‐methylation of DNA in naïve CD4 + T lymphocytes …”