title: Mechanistic target of rapamycin complex 1 is critical for invariant natural killer T-cell development and effector function.
abstract: The mechanisms that control invariant natural killer T (iNKT)-cell development and function are still poorly understood. The mechanistic or mammalian target of rapamycin (mTOR) integrates various environmental signals/cues to regulate cell growth, proliferation, metabolism, and survival. We report here that ablation of mTOR complex 1 (mTORC1) signaling by conditionally deleting Raptor causes severe defects in iNKT-cell development at early stages, leading to drastic reductions in iNKT-cell numbers in the thymus and periphery. In addition, loss of Raptor impairs iNKT-cell proliferation and production of cytokines upon α-galactosylceramide stimulation in vitro and in vivo, and inhibits liver inflammation in an iNKT cell-mediated hepatitis model. Furthermore, Raptor deficiency and rapamycin treatment lead to aberrant intracellular localization and functional impairment of promyelocytic leukemia zinc-finger, a transcription factor critical for iNKT-cell development and effector programs. Our findings define an essential role of mTORC1 to direct iNKT-cell lineage development and effector function.
authors: Departments of Pediatrics and Immunology, Duke University Medical Center, Durham, NC 27710.
authors: Jinwook
authors: J
authors: Shin
authors: Shang
authors: S
authors: Wang
authors: Wenhai
authors: W
authors: Deng
authors: Jinhong
authors: J
authors: Wu
authors: Jimin
authors: J
authors: Gao
authors: Xiao-Ping
authors: XP
authors: Zhong
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D016026:Bone Marrow Transplantation; D001973:Bromodeoxyuridine; D016923:Cell Death / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology*; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D017931:DNA Primers / Q000235:genetics; D005434:Flow Cytometry; D019672:Genes, T-Cell Receptor / Q000235:genetics; D042581:Intranuclear Space / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors / Q000276:immunology*; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D046912:Multiprotein Complexes / Q000276:immunology*; D055611:Natural Killer T-Cells / Q000276:immunology*; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D060888:Real-Time Polymerase Chain Reaction; D018709:Statistics, Nonparametric; D058570:TOR Serine-Threonine Kinases / Q000276:immunology*; D060168:Thymocytes / Q000166:cytology / Q000276:immunology*
chemical_list: D017931:DNA Primers; D051741:Kruppel-Like Transcription Factors; D046912:Multiprotein Complexes; D000075722:Promyelocytic Leukemia Zinc Finger Protein; C513267:Zbtb16 protein, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D001973:Bromodeoxyuridine
keywords: IFN-γ; IL-4; PLZF; TNFα