title: Mammalian target of rapamycin protein complex 2 regulates differentiation of Th1 and Th2 cell subsets via distinct signaling pathways.
abstract: Many functions of the mammalian target of rapamycin (mTOR) complex 1 (mTORC1) have been defined, but relatively little is known about the biology of an alternative mTOR complex, mTORC2. We showed that conditional deletion of rictor, an essential subunit of mTORC2, impaired differentiation into T helper 1 (Th1) and Th2 cells without diversion into FoxP3(+) status or substantial effect on Th17 cell differentiation. mTORC2 promoted phosphorylation of protein kinase B (PKB, or Akt) and PKC, Akt activity, and nuclear NF-kappaB transcription factors in response to T cell activation. Complementation with active Akt restored only T-bet transcription factor expression and Th1 cell differentiation, whereas activated PKC-theta reverted only GATA3 transcription factor and the Th2 cell defect of mTORC2 mutant cells. Collectively, the data uncover vital mTOR-PKC and mTOR-Akt connections in T cell differentiation and reveal distinct pathways by which mTORC2 regulates development of Th1 and Th2 cell subsets.
authors.affiliation: Department of Microbiology & Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Keunwook
authors.initials: K
authors.lastname: Lee
authors.forename: Prathyusha
authors.initials: P
authors.lastname: Gudapati
authors.forename: Srdjan
authors.initials: S
authors.lastname: Dragovic
authors.forename: Charles
authors.initials: C
authors.lastname: Spencer
authors.forename: Sebastian
authors.initials: S
authors.lastname: Joyce
authors.forename: Nigel
authors.initials: N
authors.lastname: Killeen
authors.forename: Mark A
authors.initials: MA
authors.lastname: Magnuson
authors.forename: Mark
authors.initials: M
authors.lastname: Boothby
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000276:immunology; D002469:Cell Separation; D005434:Flow Cytometry; D015151:Immunoblotting; D020287:In Situ Nick-End Labeling; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D011493:Protein Kinase C / Q000276:immunology / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000166:cytology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D018417:Th1 Cells / Q000166:cytology*; D018418:Th2 Cells / Q000166:cytology*; D014162:Transfection
chemical_list: D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D011493:Protein Kinase C