Abstract
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 (3–4 months) and aged (18–20 months) 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.
Highlights
It is generally accepted that aging is associated with altered immune response including decay in Th1-Th2-mediated immunity, diminished na€ıve T-cell-mediated de novo responses and an altered memory T-cellAccepted for publication 29 November 2013 compartment (Raynor et al, 2012)
We demonstrate that Tregs from old mice produce more IL-10, downregulate the expression of the costimulatory CD86 on dendritic cells (DCs), perturb the redox-mediated microenvironment and cause greater suppression of T-cell proliferation in comparison with Treg from young mice
As compared to young mice, release more IL-10, are more effective at downregulating CD86 expression in DCs, and modulate both the extracellular redox environment and intracellular GSH concentration in Teffs, creating conditions that are less favorable to proliferation (Supplementary Fig. S1)
Summary
It is generally accepted that aging is associated with altered immune response including decay in Th1-Th2-mediated immunity, diminished na€ıve T-cell-mediated de novo responses and an altered memory T-cellAccepted for publication 29 November 2013 compartment (Raynor et al, 2012). Immune senescence is associated with higher susceptibility to infections, autoimmunity, and cancer in the elderly (Richardson, 2002; Mendez et al, 2004; Sharma et al, 2006). While aging has been reported to be associated with increased regulatory T-cell (Treg, CD4+ CD25+) numbers, there is little information about its functional consequences on immune suppression. Two major populations of Tregs exist: the so-called natural (nTreg) and inducible (iTreg) Tregs. Excess Treg activity may lead to increased susceptibility to infection, neurodegenerative diseases, and cancer (Richardson, 2002; Mendez et al, 2004; Sharma et al, 2006)
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