title: The microRNA miR-181 is a critical cellular metabolic rheostat essential for NKT cell ontogenesis and lymphocyte development and homeostasis.
abstract: 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.
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Jorge
authors.initials: J
authors.lastname: Henao-Mejia
authors.forename: Adam
authors.initials: A
authors.lastname: Williams
authors.forename: Loyal A
authors.initials: LA
authors.lastname: Goff
authors.forename: Matthew
authors.initials: M
authors.lastname: Staron
authors.forename: Paula
authors.initials: P
authors.lastname: Licona-Limón
authors.forename: Susan M
authors.initials: SM
authors.lastname: Kaech
authors.forename: Maki
authors.initials: M
authors.lastname: Nakayama
authors.forename: John L
authors.initials: JL
authors.lastname: Rinn
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D054377:Chemokine CXCL12 / Q000378:metabolism; D015536:Down-Regulation; D006706:Homeostasis; D008214:Lymphocytes / Q000378:metabolism; D038041:Lymphopoiesis / Q000235:genetics*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D055611:Natural Killer T-Cells / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics
chemical_list: D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D035683:MicroRNAs; C529100:mirn181 microRNA, mouse; D019869:Phosphatidylinositol 3-Kinases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse