Loss of ABCG1 influences regulatory T cell differentiation and atherosclerosis
Loss of ABCG1 influences regulatory T cell differentiation and atherosclerosis
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DOI：
10.1172/jci83136
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发表时间：
2016-09-01
影响因子：
15.9
通讯作者：
Hedrick, Catherine C.
中科院分区：
文献类型：
--
作者：
Cheng, Hsin-Yuan;Gaddis, Dalia E.;Hedrick, Catherine C.
ATP结合盒转运体G1（ABCG 1）促进胆固醇积累并改变T细胞稳态，这可能有助于动脉粥样硬化的进展。在这里，我们研究了T细胞中ABCG 1的选择性丢失如何影响LDL受体缺陷（LDL受体缺陷）小鼠（一种疾病模型）的动脉粥样硬化。在喂食高胆固醇饮食的低密度脂蛋白受体缺陷小鼠中，T细胞特异性ABCG 1缺陷可防止动脉粥样硬化病变。此外，与仅LDLR缺乏的动物相比，T细胞特异性ABCG 1缺乏导致这些小鼠的主动脉和腹主动脉引流淋巴结（LN）中Treg百分比增加30%。当选择性地删除LDL受体缺陷小鼠的T细胞中的Abcg 1时，我们观察到主动脉和主动脉引流淋巴结中Treg百分比增加30%，动脉粥样硬化减少。在缺乏ABCG 1的情况下，细胞内胆固醇积累导致mTOR途径的下调，这增加了初始CD 4 T细胞向TcR的分化。T细胞活化的增加导致T细胞活化减少和T细胞产生的IL-10增加。最后，我们发现，在THBE中较高的ABCG 1表达与这些细胞在人类血液样本中的较高频率相关。我们的研究表明，ABCG 1调节T细胞分化为TcB，突出了胆固醇积累可以影响动脉粥样硬化中T细胞稳态的途径。
ATP-binding cassette transporter G1 (ABCG1) promotes cholesterol accumulation and alters T cell homeostasis, which may contribute to progression of atherosclerosis. Here, we investigated how the selective loss of ABCG1 in T cells impacts atherosclerosis in LDL receptor-deficient (LDLR-deficient) mice, a model of the disease. In LDLR-deficient mice fed a high cholesterol diet, T cell-specific ABCG1 deficiency protected against atherosclerotic lesions. Furthermore, T cell-specific ABCG1 deficiency led to a 30% increase in Treg percentages in aorta and aorta-draining lymph nodes (LNs) of these mice compared with animals with only LDLR deficiency. When Abcg1 was selectively deleted in Tregs of LDLR-deficient mice, we observed a 30% increase in Treg percentages in aorta and aorta-draining LNs and reduced atherosclerosis. In the absence of ABCG1, intracellular cholesterol accumulation led to downregulation of the mTOR pathway, which increased the differentiation of naive CD4 T cells into Tregs. The increase in Tregs resulted in reduced T cell activation and increased IL-10 production by T cells. Last, we found that higher ABCG1 expression in Tregs was associated with a higher frequency of these cells in human blood samples. Our study indicates that ABCG1 regulates T cell differentiation into Tregs, highlighting a pathway by which cholesterol accumulation can influence T cell homeostasis in atherosclerosis.