title: Cutting edge: Discrete functions of mTOR signaling in invariant NKT cell development and NKT17 fate decision.
abstract: Invariant NKT (iNKT) cells recently were classified into NKT1, NKT2, and NKT17 lineages with distinct transcription factor and cytokine profiles, but the mechanisms underlying such fate decisions remain elusive. In this article, we report crucial roles for mechanistic target of rapamycin (mTOR) signaling, especially mTORC2, in iNKT cell development and fate determination of NKT17 cells. Loss of Rictor, an obligatory component of mTORC2, decreased thymic and peripheral iNKT cells, which was associated with defective survival. Strikingly, Rictor deficiency selectively abolished the NKT17 lineage, as indicated by a marked reduction in RORγt and IL-17 expression. Moreover, deletion of phosphatase and tensin homolog (Pten) upregulated mTORC2 activity and enhanced NKT17 generation, but concomitant loss of Rictor reversed the NKT17 dysregulation. In contrast, mTORC1 regulators Raptor and Rheb are dispensable for NKT17 differentiation, despite their importance in iNKT cell thymic development. Our findings establish pivotal and unique roles for mTORC2 signaling, which is reciprocally regulated by Rictor and Pten, in NKT17 lineage determination.
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Wei
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Yang
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Hongbo
authors.initials: H
authors.lastname: Chi
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D019070:Cell Lineage / Q000235:genetics; D016130:Immunophenotyping; D051379:Mice; D018345:Mice, Knockout; D055611:Natural Killer T-Cells / Q000166:cytology* / Q000276:immunology / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; C525637:rictor protein, mouse; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase