Homeostasis and function of regulatory T cells
Division of Cellular and Molecular Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center and the University of Cincinnati, Cincinnati, OH 45229, USA. Current opinion in immunology
(Impact Factor: 7.48).
05/2012; 24(4):482-7. DOI: 10.1016/j.coi.2012.04.005
A hallmark of aging is the progressive deterioration of immune function. Age-related immune suppression increases susceptibility to infectious diseases and cancer, significant causes of morbidity and mortality in the elderly. In particular, age-related T cell dysfunction is a major contributor to 'immune-senescence'. Recently, it has become clear that the frequency of regulatory T cells (Treg) significantly increases in aged mice and humans. As Treg control the intensity of T cell responses, their accrual probably contributes to age-related immune dysfunction. This review will focus on mechanisms underlying Treg homeostasis and function in aging.
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- "There are also increased numbers of natural Tregs in lymphoid organs (but Cell Reports 12, 163–171, July 14, 2015 ª2015 The Authors 163 not the blood) (Jagger et al., 2014). It is not yet clear if Tregs from aged individuals are equally or more suppressive compared to Tregs from younger individuals (Nishioka et al., 2006; Raynor et al., 2012). Although a number of studies have assessed the total CD4 + T cell and Treg populations in the aged, it is still unclear if alterations exist in TFH and TFR cells. "
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ABSTRACT: Defective antibody production in aging is broadly attributed to immunosenescence. However, the precise immunological mechanisms remain unclear. Here, we demonstrate an increase in the ratio of inhibitory T follicular regulatory (TFR) cells to stimulatory T follicular helper (TFH) cells in aged mice. Aged TFH and TFR cells are phenotypically distinct from those in young mice, exhibiting increased programmed cell death protein-1 expression but decreased ICOS expression. Aged TFH cells exhibit defective antigen-specific responses, and programmed cell death protein-ligand 1 blockade can partially rescue TFH cell function. In contrast, young and aged TFR cells have similar suppressive capacity on a per-cell basis in vitro and in vivo. Together, these studies reveal mechanisms contributing to defective humoral immunity in aging: an increase in suppressive TFR cells combined with impaired function of aged TFH cells results in reduced T-cell-dependent antibody responses in aged mice.
Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
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- "It is found that peripheral blood CD4+CD25+Tregs accumulate dramatically in healthy aged humans and rodents –. The increase in Tregs proportion contributes to age-related immune-suppression, increases susceptibility to infectious diseases and cancer . Further, increased numbers of Tregs have been observed in patients with urinary bladder cancer (UBC), with tumor expression of FoxP3, a specific Tregs marker, correlated with clinical prognosis . "
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ABSTRACT: Regulatory T cells (Tregs) play an essential role in sustaining self-tolerance and immune homeostasis. Despite many studies on the correlation between Tregs accumulation and age, or malignancies, the related mechanism hasn't been well explored. To find out the mechanism of Tregs accumulation in aged urinary bladder cancer, we examined the novel cellular senesence gene SENEX and relevant apoptosis gene mRNA expression in sorted CD4+CD25(hi) Tregs from aged UBC donors, evaluated serum cytokine profiles related to tumor immunopathology, and further explored the relationship between SENEX expression, apoptosis gene expression and cytokine secretion. After having silenced down SENEX gene expression with RNA interference, we also evaluated the cellular apoptosis of Tregs sorted from aged UBC patients in response to H2O2-mediated stress. Our data indicated that upregulated SENEX mRNA expression in Tregs of aged UBC patients was correlated with pro-apoptotic gene expression and cytokine concentration. Silencing SENEX gene expression increased cellular apoptosis and pro-apoptotic gene expression of Tregs, in response to H2O2-mediated stress. Upregulated SENEX mRNA expression together with decreased pro-apoptotic gene expression and disturbances in cytokines synthesis may contribute to the Tregs proliferation and promote tumorigenesis and metastasis. Overall, upregulation of cellular senescence gene SENEX, was associated to regulatory T cells accumulation in aged urinary bladder cancer. Our study provides a new insight into understanding of peripheral Tregs accumulation in aged malignancies.
Available from: Pavan Reddy
- "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-cell compartment (Raynor et al., 2012). Consequently, 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). "
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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 co-culture 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. This article is protected by copyright. All rights reserved.
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