Loss of ABCG1 influences regulatory T cell differentiation and atherosclerosis. J Clin Invest 2016 Sep 01;126(9):3236-46
Date
08/03/2016Pubmed ID
27482882Pubmed Central ID
PMC5004951DOI
10.1172/JCI83136Scopus ID
2-s2.0-84987849199 (requires institutional sign-in at Scopus site) 56 CitationsAbstract
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.
Author List
Cheng HY, Gaddis DE, Wu R, McSkimming C, Haynes LD, Taylor AM, McNamara CA, Sorci-Thomas M, Hedrick CCAuthor
Mary Sorci Thomas PhD Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AdultAged
Aged, 80 and over
Animals
Aorta
Atherosclerosis
CD4-Positive T-Lymphocytes
Cell Differentiation
Cell Proliferation
Cholesterol
Disease Progression
Female
Forkhead Transcription Factors
Humans
Interleukin-10
L-Selectin
Lipoproteins
Lymph Nodes
Male
Membrane Microdomains
Mice
Mice, Inbred C57BL
Mice, Knockout
Middle Aged
Phenotype
Receptors, LDL
Signal Transduction
T-Lymphocytes, Regulatory
