Available online at www.sciencedirect.com Adaptive T cell immune responses and atherogenesis Soraya Taleb, Alain Tedgui and Ziad Mallat Atherosclerosis is a chronic inflammatory disease of the arterial wall where both innate and adaptive immune responses contribute to disease initiation and progression. Initial studies have focused on the role of T helper-1 (Th1) and Th2 responses in atherosclerosis, and more recently evidence has been published supporting a protective role of regulatory T cells in this disease. A third member of the T helper set, IL-17- producing T cells, now called Th17 cells, was recently described as a distinct lineage that play important role in autoimmune diseases. Here, we review the current knowledge on the role of effector and regulatory T cell responses in atherosclerosis and discuss the contribution of the Th17 to this disease. Address Inserm U970, Paris Cardiovascular Research Center, 56, rue Leblanc, 75015 Paris, France Corresponding author: Mallat, Ziad (ziad.mallat@inserm.fr) Current Opinion in Pharmacology 2010, 10:197–202 This review comes from a themed issue on Cardiovascular and renal Edited by Ralf P Brandes Available online 5th March 2010 1471-4892/$ – see front matter # 2010 Elsevier Ltd. All rights reserved. DOI 10.1016/j.coph.2010.02.003 It is now well recognized that atherosclerosis is driven by a chronic inflammatory process within the arterial wall initiated mainly in response to endogenously modified structures, particularly oxidized lipoproteins that stimu- late both innate and adaptive immune responses [1,2  ]. The innate response starts by vessel wall and monocyte/ macrophage activation, rapidly followed by an adaptive immune response to an array of potential antigens pre- sented to effector T lymphocytes by antigen-presenting cells. Both innate and adaptive immune responses play important roles in the initiation and development of atherosclerosis as shown using different animal models. In particular, the profound reduction of macrophages in mice deficient for macrophage colony-stimulating factor (M-CSF) protects from atherosclerosis [3]. Defective generation of T and B cells also significantly inhibits lesion development [4,5]. In response to the local milieu of cytokines, CD4 + T lymphocytes differentiate into a T helper (Th) 1 or Th2 lineage. Besides producing specific cytokines of each pathway, Th1 and Th2 cells can promote humoral immune responses to specific antigens by stimulating the production of different immunoglo- bulin subtypes. Production of IgG1 antibodies depends on Th2-type CD4 + T cells, whereas induction of IgG2a requires Th1 cells. Little data exist regarding the precise role of CD8 + T cells in atherogenesis. Like CD4+ cells, CD8+ T cells appear to promote atherogenesis in situ- ations that activate this cell subset [6–8]. In this review, we will summarize the current knowledge on the role of effector CD4+ T cells (Th1 and Th2) and regulatory T cells in atherosclerosis with a particular focus on the new lineage, Th17. Th1 response in atherosclerosis All factors involved in the Th1 response, including T-bet expression, IFN-g production as well as factors known to induce its secretion such as IL-12 and IL-18 were shown to promote atherosclerosis (reviewed in [9]). In particular, deficiency in T-bet, IFN-g R, or IFN-g significantly reduces lesion development and defective IFN-g sig- naling enhances plaque collagen content [10–12]. In contrast, exogenous administration of IFN-g accelerates lesion development [11]. IFN-g is known to activate monocytes/macrophages and DCs, leading to perpetu- ation of the pathogenic Th1 response. In addition, IFN-g may inhibit vascular smooth muscle cell proliferation and reduce their collagen production while upregulating the expression of matrix metalloproteinases, thereby contri- buting to the thinning of the fibrous cap [1]. Collectively, these data provide convincing arguments for a potent pro- atherogenic effect of IFN-g. In addition, CD40–CD40L interactions which promote Th1 development are involved in atherosclerosis (reviewed in [13]). Recently, it was shown that mice deficient in CD40 and its associ- ated signaling intermediates, tumor necrosis factor re- ceptor-associated factor (TRAF6) but not CD40– TRAF2/3/5 signaling abolishes atherosclerosis and con- fers plaque stability in Apoe / mice [14  ]. Th2 response in atherosclerosis Th2 cells secrete IL-4, IL-5, IL-10, and IL-13 and also activate B cells to produce antibodies. Th2 response was proposed to antagonize pro-atherogenic Th1 effects and thereby confer atheroprotection. However, the role of the Th2 pathway in the development of atherosclerosis remains controversial depending on the stage and/or site of the lesion, the type of Th2-secreted factor as well as the experimental model. For example, the role of IL-4 in atherosclerosis remains controversial. In LDLR / mice, deficiency in IL-4 had no substantial effect on lesion development in one study [15] but was associated with a www.sciencedirect.com Current Opinion in Pharmacology 2010, 10:197–202