Abstract 15005: PI3-Kinase δ-Deficiency in Regulatory T Cells Aggravates Atherosclerosis in LDLR-/- Mice
Atherosclerosis is a chronic inflammatory disease of arteries and represents the main underlying cause of death worldwide. Although macrophages outnumber other leukocytes in atherosclerotic lesions, T-helper 1 (Th1) cells and regulatory T cells (Tregs) can shape the course of disease by possessing inflammatory and regulatory functions. T cells express the catalytic phosphoinositide 3-kinase isoform p110δ (PI3Kδ), exerting a key role in the regulation of immune responses including activation, differentiation and effector function. Since Th1 cells and Tregs play a crucial role in atherosclerosis, we aimed to understand the role of PI3Kδ in T cells during atherogenesis. Therefore, we transplanted PI3Kδ-/- or PI3Kδ+/+ bone marrow into atherogenic diet-fed LDLR-/- mice. Hypercholesterolemic PI3Kδ-/- recipient LDLR-/- mice displayed strongly impaired CD4+ T-cell activation and proatherogenic Th1 responses as well as profoundly reduced numbers of atheroprotective Tregs in paraaortic lymph nodes and spleen compared with PI3Kδ+/+ transplanted controls. Surprisingly, the net effect of PI3Kδ-deficiency was a substantial aggravation of atherosclerosis in LDLR-/- mice. Atherosclerotic lesion area at the aortic root and whole aorta of PI3Kδ-/- recipient LDLR-/- mice was significantly increased by 72% and 118% compared with PI3Kδ+/+ recipients, respectively (n = 12-22; P < 0.001). Atherosclerotic lesions of PI3Kδ-/- transplanted LDLR-/- mice were characterized by a lower fraction of CD4+ T cells and a higher proportion of macrophages compared with controls. Whereas PI3Kδ-deficiency had only a modest impact on circulating monocytes and macrophage function including foam cell formation, efferocytosis and polarization, PI3Kδ-deficient Tregs exhibited strongly impaired immunosuppressive capabilities. Consequently, adoptive transfer of PI3Kδ+/+ Tregs into PI3Kδ-/- transplanted LDLR-/- mice rescued the atherosclerotic phenotype of PI3Kδ-/- transplanted LDLR-/- animals. In summary, we demonstrate that PI3Kδ plays a crucial role in both Th1 cells and Tregs during atherogenesis. Lack of PI3Kδ signaling in atheroprotective Treg responses outplays its impact on proatherogenic Th1 responses, thus leading to aggravated atherosclerosis.
Author Disclosures: M. Zierden: None. C. Millarg: None. M. Vantler: None. E. Berghausen: None. S. Baldus: None. S. Rosenkranz: None.
- © 2016 by American Heart Association, Inc.