Loss of ABCG1 influences regulatory T cell differentiation and atherosclerosis
Hsin-Yuan Cheng, … , Mary Sorci-Thomas, Catherine C. Hedrick
Hsin-Yuan Cheng, … , Mary Sorci-Thomas, Catherine C. Hedrick
Published August 2, 2016
Citation Information: J Clin Invest. 2016;126(9):3236-3246. https://doi.org/10.1172/JCI83136.
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Research Article Inflammation

Loss of ABCG1 influences regulatory T cell differentiation and atherosclerosis

Abstract

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.

Authors

Hsin-Yuan Cheng, Dalia E. Gaddis, Runpei Wu, Chantel McSkimming, LaTeira D. Haynes, Angela M. Taylor, Coleen A. McNamara, Mary Sorci-Thomas, Catherine C. Hedrick

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Figure 5

Mice with FOXP3-specific deficiency of ABCG1 show decreased atherosclerosis and an increase in Tregs and IL-10.

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Mice with FOXP3-specific deficiency of ABCG1 show decreased atherosclero...
(A) Expression of Abcg1 mRNA was undetectable in Tregs sorted from the blood of Foxp3-Cre+ Abcg1fl/fl Ldlr–/– mice. Results are shown for individual mice. N = 4–5 mice per group. (B–C) Foxp3-Cre+ Abcg1fl/fl Ldlr–/– and Ldlr–/– control mice were fed a high-cholesterol diet for 15 weeks, and the atherosclerotic lesion area in aortae (B) and Treg percentages in the aortic LNs (C) were analyzed. (B) Representative oil red O staining (red) in the aortic arches of Ldlr–/– and Foxp3-Cre+ Abcg1fl/fl Ldlr–/– mice. Graph shows the quantification of the lesion area as a percentage of aortic surface area in matched Ldlr–/– control and Foxp3-Cre+ Abcg1fl/fl Ldlr–/– mice after 15 weeks of high-cholesterol diet feeding. Results are shown for individual mice. N = 13–15 (B) or 6 (C) mice per group. (D–E) Foxp3-Cre+ Abcg1fl/fl Ldlr–/– mice and Foxp3-Cre+ Ldlr–/– controls were fed a high-cholesterol diet for 15 weeks, and the capacity of CD4 T cells to produce IL-10 (D) and IL-17 (E) was determined in aortic LNs following 4 hours of stimulation with PMA and ionomycin. Data shown represent individual mice. N = 5–7 mice per group. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001, by unpaired Student’s t test to determine differences between 2 groups.