Loss of ABCG1 influences regulatory T cell differentiation and atherosclerosis

• Published in: The Journal of clinical investigation Vol. 126; no. 9; pp. 3236 - 3246
• Main Authors: Cheng, Hsin-Yuan, Gaddis, Dalia E., Wu, Runpei, McSkimming, Chantel, Haynes, LaTeira D., Taylor, Angela M., McNamara, Coleen A., Sorci-Thomas, Mary, Hedrick, Catherine C.
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.09.2016
• Subjects: ABC transporters; Adult; Aged; Aged, 80 and over; Analysis; Animals; Aorta - metabolism; Atherosclerosis; Atherosclerosis - metabolism; ATP Binding Cassette Transporter, Subfamily G, Member 1 - genetics; ATP Binding Cassette Transporter, Subfamily G, Member 1 - metabolism; Biomedical research; Care and treatment; CD4-Positive T-Lymphocytes - cytology; Cell Differentiation; Cell growth; Cell Proliferation; Cholesterol; Cholesterol - metabolism; Cloning; Colleges & universities; Comparative analysis; Complications and side effects; Development and progression; Diabetes; Disease Progression; Experiments; Female; Forkhead Transcription Factors - metabolism; Gene expression; Homeostasis; Human subjects; Humans; Immunology; Inflammation; Interleukin-10 - metabolism; L-Selectin - metabolism; Laboratory animals; Lipoproteins - blood; Lymph Nodes - pathology; Lymphocytes; Male; Membrane Microdomains; Mice; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; Phenotype; Plasma; Receptors, LDL - genetics; Risk factors; Rodents; Signal Transduction; Software; T cell receptors; T-Lymphocytes, Regulatory - cytology; California
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI83136

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.