Specific Loss of ABCA1 (ATP-Binding Cassette Transporter A1) Suppresses TCR (T-Cell Receptor) Signaling and Provides Protection Against Atherosclerosis

Background: ABCA1 (ATP-binding cassette transporter A1) mediates cholesterol efflux to apo AI to maintain cellular cholesterol homeostasis. The current study aims to investigate whether T-cell-specific deletion of ABCA1 modulates the phenotype/function of T cells and the development of atherosclerosis.

Methods: Mice with T-cell-specific deletion of ABCA1 on low-density lipoprotein receptor knockout (Ldlr^-/-) background (Abca1^CD4-/CD4-Ldlr^-/-) were generated by multiple steps of (cross)-breedings among Abca1^flox/flox, CD4-Cre, and Ldlr^-/- mice.

Results: Deletions of ABCA1 greatly suppressed cholesterol efflux to apo AI but slightly reduced membrane lipid rafts on T cells probably due to the upregulation of ABCG1. Moreover, ABCA1 deficiency impaired TCR (T-cell receptor) signaling and inhibited the survival and proliferation of T cells as well as the formation of effector memory T cells. Despite the comparable levels of plasma total cholesterol after Western-type diet feeding, Abca1^CD4-/CD4-Ldlr^-/- mice showed significantly attenuated arterial accumulations of T cells and smaller atherosclerotic lesions than Abca1^+/+Ldlr^-/-controls, which were associated with reduced surface CCR5 (CC motif chemokine receptor 5) and CXCR3 (CXC motif chemokine receptor 3), decreased antiapoptotic Bcl-2 (B-cell lymphoma 2) and Bcl-xL (B-cell lymphoma extra-large), and hampered abilities to produce IL (interleukin)-2 and IFN (interferon)-γ by ABCA1-deficient T cells.

Conclusions: ABCA1 is essential for T-cell cholesterol homeostasis. Deletion of ABCA1 in T cells impairs TCR signaling, suppresses the survival, proliferation, differentiation, and function of T cells, thereby providing atheroprotection in vivo.