Loss of ABCG1 influences regulatory T cell differentiation and atherosclerosis

被引:67
作者
Cheng, Hsin-Yuan [1 ,5 ]
Gaddis, Dalia E. [1 ]
Wu, Runpei [1 ]
McSkimming, Chantel [2 ,3 ]
Haynes, LaTeira D. [1 ,6 ]
Taylor, Angela M. [2 ,3 ]
McNamara, Coleen A. [2 ,3 ]
Sorci-Thomas, Mary [4 ]
Hedrick, Catherine C. [1 ]
机构
[1] La Jolla Inst Allergy & Immunol, Div Inflammat Biol, La Jolla, CA 92037 USA
[2] Univ Virginia, Cardiovasc Res Ctr, Charlottesville, VA USA
[3] Univ Virginia, Div Cardiol, Charlottesville, VA USA
[4] Med Coll Wisconsin, Dept Med, Div Endocrinol, Milwaukee, WI 53226 USA
[5] Compugen Inc, San Francisco, CA USA
[6] Los Angeles Unified Sch Dist, Los Angeles, CA USA
关键词
BINDING CASSETTE TRANSPORTER; TOLL-LIKE RECEPTORS; APOLIPOPROTEIN-A-I; CHOLESTEROL HOMEOSTASIS; DEFICIENT MACROPHAGES; PLASMA-MEMBRANE; MICE; EFFLUX; AUTOIMMUNITY; LYMPHOCYTES;
D O I
10.1172/JCI83136
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
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.
引用
收藏
页码:3236 / 3246
页数:11
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