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Are regulatory T-cells linked with aging?

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Abstract

There is increasing evidence for an active and ‘dominant’ tolerance mediated by regulatory T-cells. Out of these CD4+ ‘naturally occurring’ regulatory T-cells (TREGs) are currently the main research focus in this field. TREGs exert their suppressive function in vitro in a contact-dependent manner and preferentially express high levels of CD25 and the forkhead and winged-helix family transcription factor forkhead box P3 (FOXP3).

Age-related increment of the prevalences of CD4+CD25hi TREGs were described controversially, and whether such changes explain immune dysfunction in the elderly is still unclear. During aging thymic TREG output may decrease with significant loss of thymic capacity to generate new T-cells, and TREG homeostasis has been shown to be sustained by alternative pathways like peripheral generation of TREGs. An imbalance of TREG homeostasis would then predispose to immune dysfunction in aged individuals explaining their higher risk of immune-mediated diseases, cancer or infections.

Introduction

The immune system has evolved to recognize and combat infectious agents (Janeway, 1989). Ideally, immune cells would recognize and disarm pathogens but ignore self-components of our body. However, cells bearing autoreactive T-cell receptors (TCRs) may occur in case of insufficient elimination in the thymus (Goodnow et al., 2005). Peripheral tolerance is then sustained by other mechanisms such as deletion, anergy and ignorance (Klein and Kyewski, 2000, Mackay, 2000). Today there is increasing evidence for an active and ‘dominant’ tolerance mediated by regulatory T-cells (Wing et al., 2005). So far several subtypes of regulatory T-cells have been described including NKT-cells, CD8+CD25+ regulatory thymocytes, CD8+CD28− T-cells, γδ T-cells, interleukin-10 producing CD4+T-regulatory-1 cells (Tr1), TGF-β secreting T-helper 3 (Th3) cells and CD4+ ‘naturally occurring’ regulatory T-cells (TREGs) (Cosmi et al., 2003, Fehervari and Sakaguchi, 2004). TREGs are currently the main research focus in this field. They exert their suppressive function in vitro in a contact-dependent manner and preferentially express high levels of CD25 and the forkhead and winged-helix family transcription factor forkhead box P3 (FOXP3) (Itoh et al., 1999).

A panel of disorders including autoimmune diseases, chronic infections and cancer have been linked with quantitative and/or qualitative defects of TREGs (Dejaco et al., 2006, Wing et al., 2005). As most of these diseases occur more often in the aging population (Pawelec et al., 2002, Taub and Longo, 2005), the question arises whether aging influences the occurrence and/or function of these TREGs. Surprisingly, only few studies have been performed in the aging population so far and will be summarized in the following sections.

Section snippets

Definition and phenotype

There is still no consensus on the definition of human TREGs. Usually, TREGs show a high constitutive surface expression of the interleukin-2 receptor alpha chain (CD25). Accordingly, regulatory activity is enriched in these CD4+CD25hi T-cells (Baecher-Allan et al., 2001, Baecher-Allan et al., 2005). However, regulatory activity has also been demonstrated in CD4+T-cells with low or intermediate expression of CD25, and CD25 may be upregulated on non-regulatory T-cells upon activation (de Kleer

Prevalence and function of TREGs during aging

The prevalences of CD4+CD25hi TREGs have been reported to average 0.6–8.7% of CD4+T-cells in healthy adults and seem to be age-dependent (Table 1). Cord blood samples, for example, contain a higher proportion of TREGs compared to adult peripheral blood samples (range 2.3–9.5%) (Wing et al., 2002, Godfrey et al., 2005). It has been speculated that these increased levels of TREGs support fetal development of the immune system with the regulation of homeostatic proliferation of naive T-cells (

Age-related thymic degeneration and homeostasis of TREGs

TREGs are generated in the thymus by a positive selection process that involves high affinity interactions of the TCR to cortically expressed host antigens and other, not completely defined TCR independent mechanisms. Thymic stromal lymphopoietin activated CD11c-positive dendritic cells, for example, have been shown to induce TREGs in a CD80/CD86 and IL-2 dependent manner (Watanabe et al., 2005). Besides, other costimulatory molecules out of the B7 or TNF family such as CD28, PD-1, CD40L (Tai

From naive to memory cell status

CD4+FOXP3+ TREGs compromise different cellular subsets, which are considered to represent distinct developmental stages (Huehn et al., 2004, Huehn et al., 2005, Huehn and Hamann, 2005, Fontenot et al., 2005, Valmori et al., 2005). One subgroup of murine FOXP3+ TREGs expressing CD25, CD62L and CCR7, for example, preferentially homes to antigen-draining lymph nodes comparable to naive T-cells, where they efficiently inhibit induction of inflammation (Huehn et al., 2004, Fontenot et al., 2005,

Conclusions

There is increasing evidence for age-dependent development of TREGs. Accumulation of memory-like CD45RO+ TREGs may account for a trend of increased CD4+CD25hi TREGs in some studies of the elderly, and peripheral TREG production is likely to increase with the involution of the thymus. The use of more specific markers like FOXP3 will help to further characterize changes of TREG homeostasis and function in the elderly. These may be responsible for the frequent occurrence of autoimmune diseases,

Acknowledgements

We thank Dr Marc Beyer, Dr Duojia Cao, Dr Isme de Kleer, Dr Tim F. Greten, Dr David A. Hafler, Dr Yu-Min Huang, Dr Tsuyoshi Iwasaki, Dr Natalia Lewkowicz, Dr Ming-Fei Liu, Dr Olindo A. Martins-Filho, Dr Berent J. Prakken, Renato Sathler-Avelar, Dr Joachim Schultze, Dr Leonie Taams, Dr Eva Tolosa, Danielle M. Vitelli-Avelar, Dr Brigitte Wildemann and Dr Kajsa Wing for their personal communications on comparable data from their studies. This work was supported by the ‘Verein zur Förderung der

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