Objective-Atherosclerosis is a chronic autoimmune-like disease in which lipids and fibrous elements accumulate in the arterial blood vessels. T cells are present within atherosclerotic plaques, and their activation is partially dependent on costimulatory signals, which can either provide positive or negative signals that promote T-cell activation or limit T-cell responses, respectively. T-cell immunoglobulin and mucin domain 3 (Tim-3) is a coinhibitory type 1 transmembrane protein that affects

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... he function of several immune cells involved in atherosclerosis, such as monocytes, macrophages, effector T cells, and regulatory T cells. In the present study, we determined the role of Tim-3 in the development of atherosclerosis. Approach and Results-Western-type diet-fed low-density lipoprotein receptor-deficient (LDLr −/− ) mice were treated with an anti-Tim-3 antibody for 3 and 8 weeks. Anti-Tim-3 administration increased fatty streak formation with 66% and increased atherosclerotic plaque formation after 8 weeks with 35% in the aortic root and with 50% in the aortic arch. Furthermore, blockade of Tim-3 signaling increased percentages of circulating monocytes with 33% and lesional macrophages with 20%. In addition, anti-Tim-3 administration increased CD4 + T cells with 17%, enhanced their activation status, and reduced percentages of regulatory T cells with 18% and regulatory B cells with 37%. Conclusions-It is known that Tim-3 acts as a negative regulator of both innate and adaptive immune responses, and in the present study, we show that anti-Tim-3 treatment augments lesion development, accompanied by an increase in the number of monocytes/macrophages and CD4 + T cells and by decreased regulatory T cells and regulatory B cells. (Arterioscler Thromb Vasc Biol. 2013;33:2558-2565.) The online-only Data Supplement is available with this article at http://atvb.ahajournals.org/lookup/suppl/ Acute cardiovascular syndromes are a major cause of death in Western society and are generally triggered by rupture of an atherosclerotic plaque. Besides lipid accumulation, an imbalance between pro-and anti-inflammatory responses plays a key role in atherosclerotic plaque development. Therefore, restoration of this balance by inhibition of proinflammatory responses and by inducing suppressor cells has great therapeutic potential to prevent cardiovascular disease. In this study, we are the first to provide direct evidence that T-cell immunoglobulin and mucin domain 3, a coinhibitory molecule that can terminate T-cell survival, cell cycle progression, and differentiation of naive T cells to effector and memory T cells, is involved in the development of atherosclerosis. Western-type diet-fed low-density lipoprotein receptordeficient mice treated with an anti-T-cell immunoglobulin and mucin domain 3 antibody showed aggravated atherosclerosis accompanied by enhanced monocytes/macrophages and effector T cells and reduced regulatory T and B cells. This study shows that promoting the T-cell immunoglobulin and mucin domain 3 pathway may represent a novel therapeutic strategy to inhibit atherosclerotic lesion development and prevent cardiovascular diseases.