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: Age-associated DNA methylation changes may alter regulatory mechanisms and signaling pathways that predispose to autoimmunity.

Keywords::

• aging
• autoimmunity
• CD4⁺ T cells
• epigenetics
• EZH2
• lupus
• methylation
• mTOR
• PRC2

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.tandfonline.com/doi/suppl/10.2217/epi-2016-0143

Financial & competing interests disclosure

Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under award number R01AI097134 and award number U19AI110502. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The institutional review boards of the participating institutions approved this study and all participants provided written, informed consent prior to enrollment.

Additional information

Funding

Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under award number R01AI097134 and award number U19AI110502. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.