title: 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.forename: Hsin-Yuan
authors.initials: HY
authors.lastname: Cheng
authors.forename: Dalia E
authors.initials: DE
authors.lastname: Gaddis
authors.forename: Runpei
authors.initials: R
authors.lastname: Wu
authors.forename: Chantel
authors.initials: C
authors.lastname: McSkimming
authors.forename: LaTeira D
authors.initials: LD
authors.lastname: Haynes
authors.forename: Angela M
authors.initials: AM
authors.lastname: Taylor
authors.forename: Coleen A
authors.initials: CA
authors.lastname: McNamara
authors.forename: Mary
authors.initials: M
authors.lastname: Sorci-Thomas
authors.forename: Catherine C
authors.initials: CC
authors.lastname: Hedrick
mesh_terms: D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1 / Q000235:genetics / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001011:Aorta / Q000378:metabolism; D050197:Atherosclerosis / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology*; D002454:Cell Differentiation; D049109:Cell Proliferation; D002784:Cholesterol / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism; D019041:L-Selectin / Q000378:metabolism; D008074:Lipoproteins / Q000097:blood; D008198:Lymph Nodes / Q000473:pathology; D008297:Male; D021962:Membrane Microdomains; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D010641:Phenotype; D011973:Receptors, LDL / Q000235:genetics; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000166:cytology
chemical_list: C419353:ABCG1 protein, human; C487540:ABCG1 protein, mouse; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D008074:Lipoproteins; D011973:Receptors, LDL; D019041:L-Selectin; D016753:Interleukin-10; D002784:Cholesterol