Statins increase the frequency of circulating CD4+ FOXP3+ regulatory T cells in healthy individuals.

Ana Lucía Rodríguez-Perea,Sven Olek,Paula A Velilla,Claire A Chougnet,Carlos J Montoya

doi:10.1155/2015/762506

Abstract

Statins have been shown to modulate the number and the suppressive function of CD4+FOXP3+ T cells (Treg) in inflammatory conditions. However, it is not well established whether statin could also affect Treg in absence of inflammation. To address this question, eighteen normocholesterolemic male subjects were treated with lovastatin or atorvastatin daily for 45 days. The frequency and phenotype of circulating Treg were evaluated at days 0, 7, 30, and 45. mRNA levels of FOXP3, IDO, TGF-β, and IL-10 were measured in CD4+ T cells. We found that both statins significantly increased Treg frequency and FOXP3 mRNA levels at day 30. At day 45, Treg numbers returned to baseline values; however, TGF-β and FOXP3 mRNA levels remained high, accompanied by increased percentages of CTLA-4- and GITR-expressing Treg. Treg Ki-67 expression was decreased upon statin treatment. Treg frequency positively correlated with plasma levels of high-density lipoprotein cholesterol (HDL-c), suggesting a role for HDL-c in Treg homeostasis. Therefore, statins appear to have inflammation-independent immune-modulatory effects. Thus, the increase in Treg cells frequency likely contributes to immunomodulatory effect of statins, even in healthy individuals.

Highlights

Regulatory T cells (Treg) are a subpopulation of CD4+ T cells that control innate and adaptive immune responses [1]
In agreement with the previous studies showing that statins suppressed CD25 upregulation by T cells [15, 16], we found decreased percentage of CD25+ cells within the CD4+FOXP3+ population at all time points compared to baseline (Figure 2(c))
Our results point to an effect of statins in vivo in noninflammatory situations/patients, affecting both the frequency and phenotype of the Treg subset, which could be associated with the increase in high-density lipoprotein cholesterol (HDL-c) levels

Summary

Introduction

Regulatory T cells (Treg) are a subpopulation of CD4+ T cells that control innate and adaptive immune responses [1] These cells have two main origins: they are either thymus-derived or peripheral-derived (tTreg and pTreg, resp.) [2]. The direct effect of statins on the immune system is difficult to establish in these statin-treated patients with chronic inflammatory diseases due to multiple confounding factors. In these previous studies, Treg frequency was measured only before and after weeks of treatment, which does not give an in-depth picture of the dynamic of the Treg response to statin treatment. Treg were studied at several time points following treatment initiation

Materials and Methods

Findings

Conclusion