ReviewHomeostasis and the functional roles of CD4+ Treg cells in aging
Introduction
Aging is a complex process associated with multiple physiological alterations, including age-related changes in the immune system such as thymic involution, development of chronic inflammation, decline in the number of naïve T cells, and modification of the functional activity of individual immune cell populations.
Of particular interest is the subset of CD4+ regulatory T (Treg) cells, which maintain immunological self-tolerance and homeostasis. Human Tregs represent 5–10% of the total CD4+ pool. Human CD4+ Tregs can be divided into two key subpopulations: thymus-derived Tregs (tTregs) and Tregs generated in the periphery (pTregs) [1,2]. The phenotype of Treg subsets is now described using a wide range of membrane and intracellular molecules (Table 1) [[2], [3], [4], [5]].
The most specific marker for Tregs is the transcription factor forkhead box P3 (FOXP3). The FOXP3 gene and its product named Scurfin are involved in the regulation of Treg cell differentiation and function. Furthermore, steadily high expression of this gene is needed for Tregs to exert their suppressive activity [2,6].
FOXP3+ Tregs are constitutively expressed high levels of membrane marker CD25 (IL-2 receptor α-chain) [2] and characterized by a low expression of the CD127 (IL-7 receptor α-chain) [7].
CD25 and CD127 cannot be considered as specific Treg cell markers since their expression may vary significantly between cell types and during cell activation. Identification of Tregs currently relies on combinations of cell surface molecules (CD4, CD25, CD127), intracellular FOXP3 with markers associated with Treg function (CTLA-4, GITR, TGF-β, CD39, PD-1 etc.) [2,8].
Thus, Tregs are heterogeneous, share common phenotypic markers (CD25, FOXP3, CD127low) and exhibit suppressive activity towards various types of immune cells. Tregs can target functions of T cells and B cells, natural killers, antigen-presenting cells. The functional specialization of Tregs enables this population to control the numerous immune reactions and maintain tissue homeostasis [2].
Several studies have shown that some age-related diseases (cancer, autoimmunity, viral infections etc.) are accompanied by changes in the number or function of Tregs [5,7,[9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20]]. Given these data, the study of changes in the functional state of the Treg population in aging is of great interest.
Section snippets
Treg cell differentiation and homeostasis in aging
The status of the tTreg and pTreg cell populations is controlled by a number of mechanisms influencing T cells and the immune system in general. One of the key events in postnatal ontogeny is thymic involution, which causes a progressive decline in the differentiation and peripheral expansion of naïve T cells [21]. Thymic epithelium annually loses an average of 3% of its weight, and the production of new T cell clones drops considerably at the age of 35–45 years. According to some estimates,
Treg cell numbers and function in aging and age-related diseases
Despite considerable interest in the study of Tregs, there is little data on the role of this subset in aging. Some studies reported an increase in the number of Tregs in the elderly [33,[50], [51], [52]], whereas others did not reveal any reliable change in Treg numbers with age [[53], [54], [55]]. However, most studies have shown an increase in aged Treg cell frequency (Table 2).
One of the key characteristics of Tregs is their ability to dampen immune responses by suppressing the activation
Immunosenescence, inflammaging and “reprogramming” of Tregs
Aging of the immune system is closely related to immunosenescence and inflammaging. Genetic, epigenetic and environmental factors are involved in immunosenescence, a complex process, characterized by a “remodeling” of the immune system with aging and generally defined as immune insufficiency or failure. Inflammaging is another aging-related phenomenon associated with a chronic, low-grade inflammation [65,66]. Both immunosenescence and inflammaging are significantly affecting the Treg pool.
As
Conclusions and future directions
An intrinsic part of the natural aging process is the emergence of a set of changes in the immune system, which has been termed immunosenescence. These patterns in immune system functioning can, with age, lead to adverse consequences for the organism: higher susceptibility to infections, inadequate immune response to vaccination, predisposition for autoimmune reactions and, possibly, for the development of malignant neoplasms.
These processes are largely controlled by Tregs. More and more
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgement
The study was funded from the federal budget under state order to Karelian Research Centre (project ID 0218-2019-0083; Modification of transcription programs of regulatory T cell differentiation in immunoinflammatory diseases and cancer).
References (86)
- et al.
A comprehensive review on the role of co-signaling receptors and Treg homeostasis in autoimmunity and tumor immunity
J. Autoimmun.
(2018) - et al.
Higher frequency of regulatory T cells in the elderly and increased suppressive activity in neurodegeneration
J. Neuroimmunol.
(2007) - et al.
The imbalance of Th17/Treg in patients with uterine cervical cancer
Clin. Chim. Acta
(2011) - et al.
Human FoxP3+ regulatory T cells in systemic autoimmune diseases
Autoimmun. Rev.
(2011) - et al.
Increased peripheral CD4+ regulatory T cells persist after successful direct-acting antiviral treatment of chronic hepatitis C
J. Hepatol.
(2017) - et al.
Thymic involution and immune reconstitution
Trends Immunol.
(2009) - et al.
The Th17/Treg balance is disturbed during aging
Exp. Gerontol.
(2013) - et al.
Induction of regulatory T cells: a role for probiotics and prebiotics to suppress autoimmunity
Autoimmun. Rev.
(2016) - et al.
Foxp3 transcription-factor-dependent and -independent regulation of the regulatory T cell transcriptional signature
Immunity
(2007) - et al.
T cell receptor stimulation-induced epigenetic changes and Foxp3 expression are independent and complementary events required for Treg cell development
Immunity
(2012)