期刊
AGING CELL
卷 13, 期 3, 页码 441-448出版社
WILEY
DOI: 10.1111/acel.12191
关键词
aging; epigenetics; methylation; redox; regulatory T cell
资金
- NIH [AG020628, AG028268, HL58984]
- University of Michigan Claude D. Pepper Older American Independence Center [AG024824]
- Nathan Shock Center for the Basic Biology of Aging [AG013283]
- Center for the Study of Lifestage Exposures and Adult Disease [ES017885]
- Caner Center Microarray Core
- Michigan Diabetes and Research Training Center Animal Phenotyping Core
- Geriatrics Research, Education and Clinical Care Center (GRECC) of the VA Ann Arbor Healthcare System
Regulatory T-cell (Treg, CD4+CD25+) dysfunction is suspected to play a key role in immune senescence and contributes to increased susceptibility to diseases with age by suppressing T-cell responses. FoxP3 is a master regulator of Treg function, and its expression is under control of several epigenetically labile promoters and enhancers. Demethylation of CpG sites within these regions is associated with increased FoxP3 expression and development of a suppressive phenotype. We examined differences in FoxP3 expression between young (3-4months) and aged (18-20months) C57BL/6 mice. DNA from CD4+ T cells is hypomethylated in aged mice, which also exhibit increased Treg numbers and FoxP3 expression. Additionally, Treg from aged mice also have greater ability to suppress effector T-cell (Teff) proliferation in vitro than Tregs from young mice. Tregs from aged mice exhibit greater redox remodeling-mediated suppression of Teff proliferation during coculture with DCs by decreasing extracellular cysteine availability to a greater extent than Tregs from young mice, creating an adverse environment for Teff proliferation. Tregs from aged mice produce higher IL-10 levels and suppress CD86 expression on DCs more strongly than Tregs from young mice, suggesting decreased T-cell activity. Taken together, these results reveal a potential mechanism of higher Treg-mediated activity that may contribute to increased immune suppression with age.
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