Please cite this article in press as: Mausner-Fainberg K, et al., The effect of HMG-CoA reductase inhibitors on naturally occurring CD4 + CD25 + T cells, Atherosclerosis (2007), doi:10.1016/j.atherosclerosis.2007.07.031 ARTICLE IN PRESS ATH-10057; No. of Pages 11 Atherosclerosis xxx (2007) xxx–xxx The effect of HMG-CoA reductase inhibitors on naturally occurring CD4 + CD25 + T cells  Karin Mausner-Fainberg, Galia Luboshits, Adi Mor, Sophia Maysel-Auslender, Ardon Rubinstein, Gad Keren, Jacob George ∗ The Department of Cardiology, Tel Aviv Sourasky Medical Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel Received 12 May 2007; received in revised form 12 July 2007; accepted 27 July 2007 Abstract Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are in widespread use due to their LDL reducing proper- ties and concomitant improvement of clinical outcome in patients with and without preexisting atherosclerosis. Considerable evidence suggests that immune mediated mechanisms play a dominant role in the beneficial effects of statins. Naturally occurring CD4 + CD25 + regulatory T cells (Tregs) have a key role in the prevention of various inflammatory and autoimmune disorders by suppressing immune responses. We tested the hypothesis that statins influence the circulating number and the functional properties of Tregs. We studied the effects of in vivo and in vitro statin treatment of human and murine mononuclear cells on the number of Tregs and the expression level of their master transcription regulator, Foxp3. Atorvastatin, but not mevastatin nor pravastatin, treatment of human peripheral blood mononuclear cells (PBMCs) increased the number of CD4 + CD25 high cells, and CD4 + CD25 + Foxp3 + cells. These Tregs, induced by atorvastatin, expressed high levels of Foxp3, which correlated with an increased regulatory potential. Furthermore, co-culture studies revealed that atorvastatin induced CD4 + CD25 + Foxp3 + Tregs were derived from peripheral CD4 + CD25 - Foxp3 - cells. Simvastatin and pravastatin treatment in hyperlipidemic subjects increased the number of Tregs. In C57BL/6 mice however, no effect of statins on Tregs was evident. In conclusion, statins appear to significantly influence the peripheral pool of Tregs in humans. This finding may shed light on the mechanisms governing the plaque stabilizing properties of statins. © 2007 Elsevier Ireland Ltd. All rights reserved. Keywords: Statins; Atherosclerosis; T cells; Immune response; Foxp3 1. Introduction Statins, the inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, are effective lipid low- ering agents that are widely used in medical practice [1]. The beneficial effect of lipid lowering by statins in the reduction of the atherosclerosis progression, and the risk of coronary heart disease as consequence, has been demonstrated in large clinical trials [2,3]. However, despite similar reduction in total  Supported by the grant from the Israel Science Foundation (JG; Grant No. 832/06). ∗ Corresponding author. Fax: +972 3 5469832. E-mail address: jacobg@post.tau.ac.il (J. George). cholesterol, it appears that the benefits of statins exceed those of other lipid-lowering agents [3,4]. This observation is one of the findings that led to the contention that statins exert addi- tional beneficial effects, independent of lipid lowering, that have been ascribed to their modulating effect on the immune system [3–6]. As it is well established that the immune sys- tem plays an active role in the pathogenesis of atherosclerosis [7,8], attenuation of the atheroma and its stabilization by statins could be also attributed to their immunomodulatory properties [9]. Atorvastatin and pravastatin were found to attenuate T cell activation and proliferation, to inhibit the secretion of the pro-inflammatory cytokines and to enhance the secre- tion of anti-inflammatory cytokines [10,11]. Two principal 0021-9150/$ – see front matter © 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosis.2007.07.031