The MicroRNA miR-181 Is a Critical Cellular Metabolic Rheostat Essential for NKT Cell Ontogenesis and Lymphocyte Development and Homeostasis

• Published in: Immunity (Cambridge, Mass.) Vol. 38; no. 5; pp. 984 - 997
• Main Authors: Henao-Mejia, Jorge, Williams, Adam, Goff, Loyal A., Staron, Matthew, Licona-Limón, Paula, Kaech, Susan M., Nakayama, Maki, Rinn, John L., Flavell, Richard A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 23.05.2013; Elsevier Limited
• Subjects: Animals; Cell Differentiation; Chemokine CXCL12 - metabolism; Down-Regulation; Homeostasis; Kinases; Lymphocytes - metabolism; Lymphopoiesis - genetics; Metabolism; Mice; MicroRNAs; MicroRNAs - genetics; MicroRNAs - metabolism; Natural Killer T-Cells - metabolism; Phosphatase; Phosphatidylinositol 3-Kinases - metabolism; PTEN Phosphohydrolase - metabolism; Rodents; Signal Transduction - genetics; Statistical analysis; T cell receptors
• ISSN: 1074-7613; 1097-4180; 1097-4180
• DOI: 10.1016/j.immuni.2013.02.021

Regulation of metabolic pathways in the immune system provides a mechanism to actively control cellular function, growth, proliferation, and survival. Here, we report that miR-181 is a nonredundant determinant of cellular metabolism and is essential for supporting the biosynthetic demands of early NKT cell development. As a result, miR-181-deficient mice showed a complete absence of mature NKT cells in the thymus and periphery. Mechanistically, miR-181 modulated expression of the phosphatase PTEN to control PI3K signaling, which was a primary stimulus for anabolic metabolism in immune cells. Thus miR-181-deficient mice also showed severe defects in lymphoid development and T cell homeostasis associated with impaired PI3K signaling. These results uncover miR-181 as essential for NKT cell development and establish this family of miRNAs as central regulators of PI3K signaling and global metabolic fitness during development and homeostasis. •miR-181 regulates cellular metabolic fitness required for robust proliferation•miR-181 is essential for NKT cell development•miR-181 is a PTEN rheostat and a central regulator of the PI3K pathway in vivo•miR-181 is a critical regulator of lymphocyte development and homeostasis