Abstract 61: T Cell--Specific Deficiency of ABCG1 Protects Against Atherosclerosis

Abstract

ATP-binding cassette transporter G1 (ABCG1) promotes cholesterol efflux from peripheral cells to HDL particles, which transport cholesterol to liver for processing for excretion. ABCG1, and not ABCA1, was found to be critical for the proliferation of T lymphocytes. Despite this, to date, very little is known about the role of ABCG1 in T cells during atherogenesis. In this study, we aim to understand how ABCG1 regulates T cell function and how absence of ABCG1 selectively in T cells impacts atherosclerosis. We found that, on a high cholesterol diet, mice with T cell-specific ABCG1 deficiency on the LDLR -/- background (LCK-Cre + /ABCG1 fl/fl /LDLR -/- ) developed 40% less atherosclerotic lesions than their littermate controls (LCK-Cre - /ABCG1 fl/fl /LDLR -/- ) (P<0.0001). Furthermore, we found that the percentage of CD4 + CD25 + Foxp3 + regulatory T cells was increased in the LCK-Cre + /ABCG1 fl/fl /LDLR -/- mice compared to the littermate controls (P<0.01). Since Tregs are considered anti-atherogenic, we hypothesize that the deficiency of ABCG1 in T cells confers changes in Tregs, which exerts our observed atheroprotective effect. We found that Tregs are hyperproliferative in the LCK-Cre + /ABCG1 fl/fl /LDLR -/- mice. We have also found increased conversion of naïve CD4 + T cells into Tregs in the LCK-Cre + /ABCG1 fl/fl /LDLR -/- mice both in vivo and in vitro . Furthermore, the Treg proliferation and differentiation can both be enhanced by the addition of excess cholesterol in vitro . To determine if deficiency of ABCG1 in Treg cells alone is sufficient to drive their induction, we examined the T cell compartment in wild-type and Treg-specific ABCG1 deletion mice (Foxp3-Cre + /ABCG1 fl/fl ). The percentage of Tregs in Foxp3-Cre + /ABCG1 fl/fl mice was significantly higher than that of wild-type controls (P<0.01). In short, we have provided evidence that ABCG1 deficiency in T cells leads to decreased atherosclerosis and induction of Tregs. By tying these two findings together, our study provides novel insights in sterol-mediated regulation of Tregs and its impact on atherosclerosis.