Elsevier

Immunology Letters

Volume 226, October 2020, Pages 83-89
Immunology Letters

Review
Homeostasis and the functional roles of CD4+ Treg cells in aging

https://doi.org/10.1016/j.imlet.2020.07.004Get rights and content

Highlights

  • Regulatory T cells are important in the maintenance of immune homeostasis.

  • Most studies show an increase in the number of Tregs with age.

  • In general, data indicate equal or increased functional activity of Tregs with age.

  • An imbalance of Treg subset may increase the risk of developing of age-related diseases.

Abstract

Objective

An upward trend in life expectancy has been observed in a majority of developed countries and leading to increasing in aging-related diseases. Aging is a risk factor for the development of widespread clinical conditions such as cardiovascular and autoimmune diseases, cancer, infections. Although studies have been very active, the problem of aging still remains one of the most obscure aspects of human biology.

Regulatory T (Treg) cells with immunosuppressive properties have a pivotal role in the maintenance of immune homeostasis. Alterations in Treg cell functionality appear to be of great importance in the development of immune senescence and contribute to increased susceptibility to immune-mediated diseases with age.

Design

This review highlights recent findings regarding the age-related changes in the numbers and functional activity of human Tregs. Some of the mechanisms that maintain the balance of Tregs during human aging are discussed. The possible roles of Tregs in the pathogenesis of diseases associated with advanced age are also considered.

Results

Age-related systemic changes, such as thymic involution, hormonal status, and epigenetic modifications, may affect the state of the Treg population and trigger various diseases. These changes involve decline or amplification in the functional activity of Tregs, an increase in the memory Treg subset and shifting of a Th17/Treg balance.

Conclusion

Taken together, the reviewed data suggest equal or even increased Treg functionality with age. Thus, age-mediated Treg expansion and higher Treg activity may contribute to elevated immune suppression and increased risk of infections and cancer.

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)

  • L.F. Lu et al.

    Foxp3-dependent microRNA155 confers competitive fitness to regulatory T cells by targeting SOCS1 protein

    Immunity

    (2009)
  • J.E. Gottenberg et al.

    CD4+CD25high regulatory T cells are not impaired in patients with primary Sjögren`s syndrome

    J. Autoimmun.

    (2005)
  • P. Trzonkowski et al.

    CD4+CD25+ T regulatory cells inhibit cytotoxic activity of CTL and NK cells in humans-impact of immunosenescence

    Clin. Immunol.

    (2006)
  • K.A. Hwang et al.

    Aging and human CD4+ regulatory T cells

    Mech. Ageing Dev.

    (2009)
  • B.C. Chiu et al.

    Increased Foxp3+ Treg cell activity reduces dendritic cell co-stimulatory molecule expression in aged mice

    Mech. Ageing Dev.

    (2007)
  • C. Franceschi et al.

    Inflammaging and anti-inflammaging: a systemic perspective on aging and longevity emerged from studies in humans

    Mech. Ageing Dev.

    (2007)
  • M.M. Cavanagh et al.

    Chronic inflammation and aging: DNA damage tips the balance

    Curr. Opin. Immunol.

    (2012)
  • B. Weinberger et al.

    Healthy aging and latent infection with CMV lead to distinct changes in CD8+ and CD4+ T-cell subsets in the elderly

    Hum. Immunol.

    (2007)
  • K.S.M. van der Geest et al.

    Aging disturbs the balance between effector and regulatory CD4+ T cells

    Exp. Gerontol.

    (2014)
  • J. Raynor et al.

    Homeostasis and function of regulatory T cells in aging

    Curr. Opin. Immunol.

    (2012)
  • D.L. Gupta et al.

    Coexistence of Th1/Th2 and Th17/Treg imbalances in patients with post traumatic sepsis

    Cytokine

    (2016)
  • J.S. Lee et al.

    Age-associated alteration in naive and memory Th17 cell response in humans

    Clin. Immunol.

    (2011)
  • X. Ouyang et al.

    Potentiation of Th17 cytokines in aging process contributes to the development of colitis

    Cell Immunol.

    (2011)
  • M. Noack et al.

    Th17 and regulatory T cell balance in autoimmune and inflammatory diseases

    Autoimmun. Rev.

    (2014)
  • A.K. Abbas et al.

    Regulatory T cells: recommendations to simplify the nomenclature

    Nat. Immunol.

    (2013)
  • P. Georgiev et al.

    Regulatory T Cells: the many faces of Foxp3

    J. Clin. Immunol.

    (2019)
  • X. Lin et al.

    Advances in distinguishing natural from induced Foxp3(+) regulatory T cells

    Int. J. Clin. Exp. Pathol.

    (2013)
  • S. Sakaguchi et al.

    FOXP3+ regulatory T cells in the human immune system

    Nat. Rev. Immunol.

    (2010)
  • Y. Shu et al.

    Epigenetic variability of CD4+CD25+ tregs contributes to the pathogenesis of autoimmune diseases

    Clin. Rev. Allergy Immunol.

    (2017)
  • C. Liu et al.

    Targeting regulatory T cells in tumors

    FEBS J.

    (2016)
  • T. Bedke et al.

    Endothelial cells augment the suppressive function of CD4+CD25+Foxp3+ regulatory T cells: involvement of programmed death-1 and IL-10

    J. Immunol.

    (2010)
  • X.P. Nan et al.

    Circulating CD4+CD25high regulatory T cells and expression of PD-1 and BTLA on CD4+ T cells in patients with chronic hepatitis B virus infection

    Viral Immunol.

    (2010)
  • J.J. Goronzy et al.

    Immune aging and autoimmunity

    Cell Mol. Life Sci.

    (2012)
  • P.N. Kravchenko et al.

    Subpopulations of regulatory T-lymphocytes in the peripheral blood of patients with rheumatoid arthritis

    Vestn. Ross. Akad. Med. Nauk.

    (2016)
  • G.J. Walter et al.

    Phenotypic, functional, and gene expression profiling of peripheral CD45RA+ and CD45RO+CD4+CD25+CD127low treg cells in patients with chronic rheumatoid arthritis

    Arthritis Rheumatol.

    (2016)
  • G.A. Zhulai et al.

    Significance of treg cells for adenosine-mediated immune suppression in colorectal cancer

    Med. Immunol. (Russia)

    (2017)
  • P.-F. Hou et al.

    Age-related changes in CD4+CD25+FOXP3+ regulatory T cells and their relationship with lung cancer

    PLoS One

    (2017)
  • G.А. Zhulai et al.

    Activation of CD4+CD39+ T cells in colorectal cancer

    Bull. Russ. State Med. Univ.

    (2018)
  • A.V. Churov et al.

    Indices of cell-mediated immunity in rheumatoid arthritis: the role of cytomegalovirus infection

    Klin. Lab. Diagn.

    (2019)
  • J. Oh et al.

    Capacity of tTreg generation is not impaired in the atrophied thymus

    PLoS Biol.

    (2017)
  • O. Briceño et al.

    Reduced naïve CD8(+) T-cell priming efficacy in elderly adults

    Aging Cell

    (2016)
  • C. Bourgeois et al.

    Age-specific T cell homeostasis

  • L. Lu et al.

    Characterization of protective human CD4+CD25+FOXP3+ regulatory T cells generated with IL-2, TGF-β and retinoic acid

    PLoS One

    (2010)
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