title: Mammalian target of rapamycin complex 2 regulates invariant NKT cell development and function independent of promyelocytic leukemia zinc-finger.
abstract: The mammalian target of rapamycin (mTOR) senses and incorporates different environmental cues via the two signaling complexes mTOR complex 1 (mTORC1) and mTORC2. As a result, mTOR controls cell growth and survival, and also shapes different effector functions of the cells including immune cells such as T cells. We demonstrate in this article that invariant NKT (iNKT) cell development is controlled by mTORC2 in a cell-intrinsic manner. In mice deficient in mTORC2 signaling because of the conditional deletion of the Rictor gene, iNKT cell numbers were reduced in the thymus and periphery. This is caused by decreased proliferation of stage 1 iNKT cells and poor development through subsequent stages. Functionally, iNKT cells devoid of mTORC2 signaling showed reduced number of IL-4-expressing cells, which correlated with a decrease in the transcription factor GATA-3-expressing cells. However, promyelocytic leukemia zinc-finger (PLZF), a critical transcription factor for iNKT cell development, is expressed at a similar level in mTORC2-deficient iNKT cells compared with that in the wild type iNKT cells. Furthermore, cellular localization of PLZF was not altered in the absence of mTOR2 signaling. Thus, our study reveals the PLZF-independent mechanisms of the development and function of iNKT cells regulated by mTORC2.
authors.affiliation: Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109;
authors.forename: Nicolas
authors.initials: N
authors.lastname: Prevot
authors.affiliation: Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109;
authors.forename: Kalyani
authors.initials: K
authors.lastname: Pyaram
authors.affiliation: Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109;
authors.forename: Evan
authors.initials: E
authors.lastname: Bischoff
authors.affiliation: Laboratory of Molecular Biology and Immunology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224; and.
authors.forename: Jyoti Misra
authors.initials: JM
authors.lastname: Sen
authors.affiliation: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Powell
authors.affiliation: Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109; heechang@umich.edu.
authors.forename: Cheong-Hee
authors.initials: CH
authors.lastname: Chang
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology*; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D050990:GATA3 Transcription Factor / Q000096:biosynthesis*; D007371:Interferon-gamma / Q000096:biosynthesis; D020381:Interleukin-17 / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D051741:Kruppel-Like Transcription Factors / Q000096:biosynthesis*; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000235:genetics / Q000276:immunology*; D055611:Natural Killer T-Cells / Q000166:cytology* / Q000276:immunology; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology*
chemical_list: D002352:Carrier Proteins; D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D020381:Interleukin-17; D051741:Kruppel-Like Transcription Factors; D046912:Multiprotein Complexes; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; C513267:Zbtb16 protein, mouse; C525637:rictor protein, mouse; D015847:Interleukin-4; D007371:Interferon-gamma; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases