title: mTORC2 regulates multiple aspects of NKT-cell development and function.
abstract: Invariant NKT (iNKT) cells bridge innate and adaptive immunity by rapidly secreting cytokines and lysing targets following TCR recognition of lipid antigens. Based on their ability to secrete IFN-γ, IL-4 and IL-17A, iNKT-cells are classified as NKT-1, NKT-2, and NKT-17 subsets, respectively. The molecular pathways regulating iNKT-cell fate are not fully defined. Recent studies implicate Rictor, a required component of mTORC2, in the development of select iNKT-cell subsets, however these reports are conflicting. To resolve these questions, we used Rictorfl/flCD4cre+mice and found that Rictor is required for NKT-17 cell development and normal iNKT-cell cytolytic function. Conversely, Rictor is not absolutely required for IL-4 and IFN-γ production as peripheral iNKT-cells make copious amounts of these cytokines. Overall iNKT-cell numbers are dramatically reduced in the absence of Rictor. We provide data indicating Rictor regulates cell survival as well as proliferation of developing and mature iNKT-cells. Thus, mTORC2 regulates multiple aspects of iNKT-cell development and function.
authors.affiliation: Abramson Family Cancer Research Center, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Tammarah
authors.initials: T
authors.lastname: Sklarz
authors.affiliation: Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Guan
authors.affiliation: Abramson Family Cancer Research Center, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Mercy
authors.initials: M
authors.lastname: Gohil
authors.affiliation: Abramson Family Cancer Research Center, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Renee M
authors.initials: RM
authors.lastname: Cotton
authors.affiliation: Department of Medicine, University of California at Davis, Davis, CA, USA.
authors.forename: Moyar Q
authors.initials: MQ
authors.lastname: Ge
authors.affiliation: Department of Medicine, University of California at Davis, Davis, CA, USA.
authors.forename: Angela
authors.initials: A
authors.lastname: Haczku
authors.affiliation: Department of Physiology, Michigan State University, East Lansing, MI, USA.
authors.forename: Rupali
authors.initials: R
authors.lastname: Das
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Martha S
authors.initials: MS
authors.lastname: Jordan
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D007113:Immunity, Innate; D008213:Lymphocyte Activation / Q000235:genetics; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000378:metabolism*; D055611:Natural Killer T-Cells / Q000502:physiology*; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics; D011828:Radiation Chimera; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D016207:Cytokines; D046912:Multiprotein Complexes; D018809:Proliferating Cell Nuclear Antigen; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; C413374:p27 antigen; C525637:rictor protein, mouse; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases
keywords: cytotoxicity; development; differentiation; natural killer T cell; signal transduction; thymus