Hypercholesterolemia Induces Differentiation of Regulatory T Cells in the Liver

• Published in: Circulation research Vol. 120; no. 11; pp. 1740 - 1753
• Main Authors: Mailer, Reiner K.W, Gisterå, Anton, Polyzos, Konstantinos A, Ketelhuth, Daniel F J, Hansson, Göran K
• Format: Journal Article
• Language: English
• Published: United States American Heart Association, Inc 26-05-2017; Lippincott Williams & Wilkins Ovid Technologies
• Subjects: Adoptive transfer; Animals; Aorta; Arteriosclerosis; Atherosclerosis; CD11b antigen; CD11c antigen; CD4 antigen; Cell Differentiation - physiology; Cholesterol; Coronary vessels; Dietary intake; Helper cells; Hepatocytes; Homeostasis; Hypercholesterolemia; Hypercholesterolemia - blood; Hypercholesterolemia - pathology; Immune clearance; Immune response; Immunoregulation; Inflammation; Lipoproteins; Liver; Liver - cytology; Liver - pathology; Liver - physiology; Low density lipoprotein receptors; Lymphocytes T; Medicin och hälsovetenskap; Mice; Mice, Inbred C57BL; Mice, Transgenic; Random Allocation; Receptor density; Rodents; T cell receptors; T-Lymphocytes, Regulatory - physiology; Transforming growth factor; atherosclerosis; inflammation; liver; transforming growth factor beta; metabolism; regulatory T-cells; hypercholesterolemia
• ISSN: 0009-7330; 1524-4571; 1524-4571
• DOI: 10.1161/CIRCRESAHA.116.310054

RATIONALE:The liver is the central organ that responds to dietary cholesterol intake and facilitates the release and clearance of lipoprotein particles. Persistent hypercholesterolemia leads to immune responses against lipoprotein particles that drive atherosclerosis. However, the effect of hypercholesterolemia on hepatic T cell differentiation remains unknown.
OBJECTIVE:To investigate hepatic T cell subsets upon hypercholesterolemia.
METHODS AND RESULTS:We observed that hypercholesterolemia elevated the intrahepatic regulatory T (Treg) cell population and increased the expression of transforming growth factor beta 1 in the liver. Adoptive transfer experiments revealed that intrahepatically differentiated Treg cells relocated to the inflamed aorta in atherosclerosis-prone low-density lipoprotein receptor deficient (Ldlr-/-) mice. Moreover, hypercholesterolemia induced the differentiation of intrahepatic, but not intrasplenic, Th17 cells in wild type mice, whereas the disrupted liver homeostasis in hypercholesterolemic Ldlr-/- mice led to intrahepatic Th1 cell differentiation and CD11b+CD11c+ leukocyte accumulation.
CONCLUSIONS:Our results elucidate a new mechanism that controls intrahepatic T cell differentiation during atherosclerosis development and indicates that intrahepatically differentiated T cells contribute to the CD4+ T cell pool in the atherosclerotic aorta.