ATP-binding cassette transporter G1 negatively regulates thymocyte and peripheral lymphocyte proliferation.
ATP-binding cassette transporter G1 negatively regulates thymocyte and peripheral lymphocyte proliferation.
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DOI：
10.4049/jimmunol.0902372
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发表时间：
2010-01-01
期刊：
影响因子：
--
通讯作者：
Hedrick CC
中科院分区：
文献类型：
--
作者：
Armstrong AJ;Gebre AK;Parks JS;Hedrick CC
胆固醇是细胞膜的关键成分，对细胞生长和增殖至关重要。细胞胆固醇的积累如何影响淋巴细胞的发育和功能尚不清楚。我们证明，ATP结合盒转运蛋白G1（ABCG 1）调节胸腺细胞和外周血CD 4 T细胞的胆固醇稳态。我们的工作是第一次描述Abcg 1缺陷小鼠中的细胞类型，其胆固醇含量和胆固醇代谢基因的表达发生如此强烈的变化。Abcg 1缺陷小鼠体内胸腺细胞和外周T淋巴细胞增殖增加。CD 4 T细胞中ABCG 1的缺乏导致体外过度增殖，但仅当细胞通过TCR刺激时。我们假设Abcg 1 −/− T细胞中的胆固醇积累改变了质膜结构，导致TCR信号传导增强，促进增殖。支持这一想法，我们证明，B6 T细胞与可溶性胆固醇预处理有显着增加增殖。Abcg 1 −/− CD 4 T细胞中的胆固醇蓄积导致ZAP 70和ERK 1/2的基础磷酸化水平增强。此外，抑制TCR刺激的Abcg 1 −/− T细胞中的ERK磷酸化可以挽救过度增殖表型。我们描述了一种新的机制，胆固醇可以改变信号从质膜影响下游信号通路和增殖。这些结果暗示ABCG 1通过维持细胞胆固醇稳态作为淋巴细胞增殖的重要负调节剂。
Cholesterol is a key component of cell membranes and is essential for cell growth and proliferation. How the accumulation of cellular cholesterol affects lymphocyte development and function is not well understood. We demonstrate that ATP-binding cassette transporter G1 (ABCG1) regulates cholesterol homeostasis in thymocytes and peripheral CD4 T cells. Our work is the first to describe a cell type in Abcg1-deficient mice with such a robust change in cholesterol content and the expression of cholesterol metabolism genes. Abcg1-deficient mice display increased thymocyte cellularity and enhanced proliferation of thymocytes and peripheral T lymphocytes in vivo. The absence of ABCG1 in CD4 T cells results in hyperproliferation in vitro, but only when cells are stimulated through the TCR. We hypothesize that cholesterol accumulation in Abcg1−/− T cells alters the plasma membrane structure, resulting in enhanced TCR signaling for proliferation. Supporting this idea, we demonstrate that B6 T cells pretreated with soluble cholesterol have a significant increase in proliferation. Cholesterol accumulation in Abcg1−/− CD4 T cells results in enhanced basal phosphorylation levels of ZAP70 and ERK1/2. Furthermore, inhibition of ERK phosphorylation in TCR-stimulated Abcg1−/− T cells rescues the hyperproliferative phenotype. We describe a novel mechanism by which cholesterol can alter signaling from the plasma membrane to affect downstream signaling pathways and proliferation. These results implicate ABCG1 as an important negative regulator of lymphocyte proliferation through the maintenance of cellular cholesterol homeostasis.
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