Gotsman Israel, Grabie Nir, Gupta Rajat, Dacosta Rosa, MacConmara Malcolm, Lederer James, Sukhova Galina, Witztum Joseph L, Sharpe Arlene H, Lichtman Andrew H
Immunology Division, Brigham and Women's Hospital, and Harvard Medical School, Boston, Mass 02115, USA.
Circulation. 2006 Nov 7;114(19):2047-55. doi: 10.1161/CIRCULATIONAHA.106.633263. Epub 2006 Oct 23.
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.
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.
ICOS has a key role in regulation of atherosclerosis, through its effect on regulatory T-cell responses.
T细胞介导的免疫反应参与动脉粥样硬化的发病机制，但对于这些反应如何被调节却知之甚少。我们探讨了诱导性共刺激分子（ICOS）对动脉粥样硬化及相关免疫反应的影响。
通过将ICOS缺陷型或野生型骨髓移植到经辐射的易患动脉粥样硬化、低密度脂蛋白受体缺陷型小鼠体内，构建骨髓嵌合体小鼠，并给予这些嵌合体小鼠高胆固醇饮食8周。与对照组相比，移植了ICOS缺陷型骨髓的小鼠动脉粥样硬化负担增加了43%，重要的是，其病变部位的CD4+ T细胞增加了3倍，同时巨噬细胞、平滑肌细胞和胶原蛋白含量也增加。与对照组小鼠的T细胞相比，来自ICOS缺陷型嵌合体小鼠的CD4+ T细胞增殖更多，分泌的干扰素-γ和肿瘤坏死因子-α也更多，这表明缺乏调节。发现FoxP3+调节性T细胞（Treg）组成性地高表达ICOS，这表明ICOS在Treg功能中发挥作用。与对照组小鼠相比，ICOS缺陷型小鼠的FoxP3+ Treg数量减少，体外Treg抑制功能受损。
ICOS通过对调节性T细胞反应的影响，在动脉粥样硬化的调节中起关键作用。
