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 -/- 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.