Mini Review Are regulatory T-cells linked with aging? Christian Dejaco, Christina Duftner, Michael Schirmer * Division of General Internal Medicine, Clinical Department of Internal Medicine, Innsbruck Medical University, Anichstrasse 35, A-6020 Innsbruck, Austria Received 28 November 2005; received in revised form 11 January 2006; accepted 24 January 2006 Available online 3 March 2006 Abstract There is increasing evidence for an active and ‘dominant’ tolerance mediated by regulatory T-cells. Out of these CD4 C ‘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 C CD25 hi 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. q 2006 Elsevier Inc. All rights reserved. Keywords: Regulatory T-lymphocyte; Aging; FOXP3; Cellular senescence; Thymus 1. 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, CD8C CD25C regulatory thymocytes, CD8 C CD28 K T-cells, gd T-cells, interleukin-10 producing CD4 C T-regulatory-1 cells (Tr1), TGF-b secreting T-helper 3 (Th3) cells and CD4 C ‘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. 2. Cellular characterisation of TREGs 2.1. 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 C CD25 hi T-cells (Baecher-Allan et al., 2001, 2005). However, regulatory activity has also been demonstrated in CD4 C T-cells with low or intermediate expression of CD25, and CD25 may be upregulated on non-regulatory T-cells upon activation (de Kleer et al., 2004; Makita et al., 2004; Shevach, 2004). Therefore, high CD25 expression alone is not sufficient Experimental Gerontology 41 (2006) 339–345 www.elsevier.com/locate/expgero 0531-5565/$ - see front matter q 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.exger.2006.01.008 * Corresponding author. Tel.: C43 512 504 0; fax: C43 512 580 435. E-mail address: michael.schirmer@uibk.ac.at (M. Schirmer).