Loss of ABCG1 influences regulatory T cell differentiation and atherosclerosis
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
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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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 6

Absence of ABCG1 results in increased cellular cholesterol and lipid rafts, inhibition of mTOR signaling, and increased p-STAT5 signaling.

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Absence of ABCG1 results in increased cellular cholesterol and lipid raf...
(A–C) Cholesterol content using filipin staining (A) p-S6 (B) and p-STAT5 (C) in Lck-Cre+ Abcg1fl/fl Ldlr–/– Tregs compared with Tregs from Lck-Cre– Abcg1fl/fl Ldlr–/– littermates. Cells were isolated from aortic LNs in A–C and were stimulated with 100 U/ml IL-2 for 15 minutes in B and C. Red line indicates Lck-Cre+ Abcg1fl/fl Ldlr–/– Tregs; black line indicates Lck-Cre– Abcg1fl/fl Ldlr–/– Tregs. An unstimulated sample is shown in gray in B and C. Results are shown for individual mice. N = 5–6 mice per group. (D) Filipin staining showed an increase in intracellular cholesterol in Tregs in aortic LNs from Foxp3-Cre+ Abcg1fl/fl Ldlr–/– mice (red) compared with Ldlr–/– control mice (black) following 15 weeks of high-cholesterol diet feeding. Results are shown for individual mice. N = 4–5 mice per group. (E–F) Foxp3-Cre+ Abcg1fl/fl Ldlr–/– and Foxp3-Cre+ Ldlr–/– control mice were fed a high-cholesterol diet for 15 weeks, and lipid rafts and p-S6 were measured in Tregs in the aortic LNs. Plots represent 2 separate experiments (Exp1 and Exp2). *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.