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CCL17-expressing dendritic cells drive atherosclerosis by restraining regulatory T-cell homeostasis in mice

Weber, Christian and Meiler, Svenja and Doering, Yvonne and Koch, Miriam and Drechsler, Maik and Megens, Remco T.A. and Rowinska, Zuzanna and Bidzhekov, Kiril and Ribechini, Eliana and van Zandvoort, Marc A.M.J. and Binder, Christoph J. and Jelinek, Ivett and Hristov, Mihail and Boon, Louis and Jung, Steffen and Korn, Thomas and Lutz, Manfred and Foerster, Irmgard and Zenke, Martin and Hieronymus, Thomas and Junt, Tobias and Zernecke, Alma (2011) CCL17-expressing dendritic cells drive atherosclerosis by restraining regulatory T-cell homeostasis in mice. Journal of Clinical Investigation, 121 (7). pp. 2898-2910. ISSN 0021-9738

Abstract

Immune mechanisms are known to control the pathogenesis of atherosclerosis, however, the exact role of dendritic cells (DCs), which are essential for priming of immune responses, remains elusive. We show that the DC-derived chemokine CCL17 is present in advanced human and mouse atherosclerosis and that CCL17+ DCs accumulate in atherosclerotic lesions. In atherosclerosis-prone mice, Ccl17 deficiency entails a reduction of atherosclerosis, which is dependent on regulatory T (Treg) cells and their expansion. Expression of CCL17 by DCs restricts the maintenance of Tregs by limiting their differentiation, proliferation and survival, precipitating atherosclerosis in a mechanism conferred by T cells. Conversely, an antibody to CCL17 expands Tregs and reduces atheroprogression. Our data identify DC-derived CCL17 as a central regulator of Treg homeostasis, implicating DCs and their effector functions in atherogenesis and introducing CCL17 as a potential target for vascular therapy.

Item Type: Article
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Keywords: chemokine, atherosclerosis, dendritic cell, T cell differentiation
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Date Deposited: 13 Oct 2015 13:15
Last Modified: 13 Oct 2015 13:15
URI: https://oak.novartis.com/id/eprint/4574

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