BACKGROUND: T-cell-mediated immunity contributes to the pathogenesis of atherosclerosis, but little is known about how these responses are regulated. We explored the influence of the inducible costimulatory molecule (ICOS) on atherosclerosis and associated immune responses. METHODS AND RESULTS: Bone marrow chimeras were generated by transplanting ICOS-deficient or wild-type bone marrow into irradiated atherosclerosis-prone, LDR receptor-deficient mice, and the chimeric mice were fed a high-cholesterol diet for 8 weeks. Compared with controls, mice transplanted with ICOS-deficient marrow had a 43% increase in the atherosclerotic burden, and importantly, their lesions had a 3-fold increase in CD4+ T cells, as well as increased macrophage, smooth muscle cell, and collagen content. CD4+ T cells from ICOS-deficient chimeras proliferated more and secreted more interferon-gamma and tumor necrosis factor-alpha than T cells from control mice, which suggests a lack of regulation. FoxP3+ regulatory T cells (Treg) were found to constitutively express high ICOS levels, which suggests a role for ICOS in Treg function. ICOS-deficient mice had decreased numbers of FoxP3+ Treg and impaired in vitro Treg suppressive function compared with control mice. CONCLUSIONS: ICOS has a key role in regulation of atherosclerosis, through its effect on regulatory T-cell responses.
BACKGROUND: T-cell-mediated immunity contributes to the pathogenesis of atherosclerosis, but little is known about how these responses are regulated. We explored the influence of the inducible costimulatory molecule (ICOS) on atherosclerosis and associated immune responses. METHODS AND RESULTS: Bone marrow chimeras were generated by transplanting ICOS-deficient or wild-type bone marrow into irradiated atherosclerosis-prone, LDR receptor-deficient mice, and the chimeric mice were fed a high-cholesterol diet for 8 weeks. Compared with controls, mice transplanted with ICOS-deficient marrow had a 43% increase in the atherosclerotic burden, and importantly, their lesions had a 3-fold increase in CD4+ T cells, as well as increased macrophage, smooth muscle cell, and collagen content. CD4+ T cells from ICOS-deficient chimeras proliferated more and secreted more interferon-gamma and tumor necrosis factor-alpha than T cells from control mice, which suggests a lack of regulation. FoxP3+ regulatory T cells (Treg) were found to constitutively express high ICOS levels, which suggests a role for ICOS in Treg function. ICOS-deficientmice had decreased numbers of FoxP3+ Treg and impaired in vitro Treg suppressive function compared with control mice. CONCLUSIONS:ICOS has a key role in regulation of atherosclerosis, through its effect on regulatory T-cell responses.
Authors: Christian Weber; Svenja Meiler; Yvonne Döring; Miriam Koch; Maik Drechsler; Remco T A Megens; Zuzanna Rowinska; Kiril Bidzhekov; Caroline Fecher; Eliana Ribechini; Marc A M J van Zandvoort; Christoph J Binder; Ivett Jelinek; Mihail Hristov; Louis Boon; Steffen Jung; Thomas Korn; Manfred B Lutz; Irmgard Förster; Martin Zenke; Thomas Hieronymus; Tobias Junt; Alma Zernecke Journal: J Clin Invest Date: 2011-07 Impact factor: 14.808
Authors: Tamson V Moore; Bryan S Clay; Judy L Cannon; Alexander Histed; Rebecca A Shilling; Anne I Sperling Journal: Am J Respir Cell Mol Biol Date: 2011-03-18 Impact factor: 6.914
Authors: Roland Klingenberg; Norbert Gerdes; Robert M Badeau; Anton Gisterå; Daniela Strodthoff; Daniel F J Ketelhuth; Anna M Lundberg; Mats Rudling; Stefan K Nilsson; Gunilla Olivecrona; Stefan Zoller; Christine Lohmann; Thomas F Lüscher; Matti Jauhiainen; Tim Sparwasser; Göran K Hansson Journal: J Clin Invest Date: 2013-02-15 Impact factor: 14.808