title: The kinase mTOR regulates the differentiation of helper T cells through the selective activation of signaling by mTORC1 and mTORC2.
abstract: The kinase mTOR has emerged as an important regulator of the differentiation of helper T cells. Here we demonstrate that differentiation into the T(H)1 and T(H)17 subsets of helper T cells was selectively regulated by signaling from mTOR complex 1 (mTORC1) that was dependent on the small GTPase Rheb. Rheb-deficient T cells failed to generate T(H)1 and T(H)17 responses in vitro and in vivo and did not induce classical experimental autoimmune encephalomyelitis (EAE). However, they retained their ability to become T(H)2 cells. Alternatively, when mTORC2 signaling was deleted from T cells, they failed to generate T(H)2 cells in vitro and in vivo but preserved their ability to become T(H)1 and T(H)17 cells. Our data identify mechanisms by which two distinct signaling pathways downstream of mTOR regulate helper cell fate in different ways. These findings define a previously unknown paradigm that links T cell differentiation with selective metabolic signaling pathways.
authors.affiliation: Sidney-Kimmel Comprehensive Cancer Research Center, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Greg M
authors.initials: GM
authors.lastname: Delgoffe
authors.forename: Kristen N
authors.initials: KN
authors.lastname: Pollizzi
authors.forename: Adam T
authors.initials: AT
authors.lastname: Waickman
authors.forename: Emily
authors.initials: E
authors.lastname: Heikamp
authors.forename: David J
authors.initials: DJ
authors.lastname: Meyers
authors.forename: Maureen R
authors.initials: MR
authors.lastname: Horton
authors.forename: Bo
authors.initials: B
authors.lastname: Xiao
authors.forename: Paul F
authors.initials: PF
authors.lastname: Worley
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Powell
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D016207:Cytokines / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D015151:Immunoblotting; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D046912:Multiprotein Complexes; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D000076205:Ras Homolog Enriched in Brain Protein; D015398:Signal Transduction; D006377:T-Lymphocytes, Helper-Inducer / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D018417:Th1 Cells / Q000378:metabolism; D058504:Th17 Cells / Q000378:metabolism; D018418:Th2 Cells / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors
chemical_list: D002352:Carrier Proteins; C504923:Crtc2 protein, mouse; D016207:Cytokines; D046912:Multiprotein Complexes; D009479:Neuropeptides; D011506:Proteins; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D000076205:Ras Homolog Enriched in Brain Protein; C490213:Rheb protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; C525637:rictor protein, mouse; C546843:mTOR protein, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020559:Monomeric GTP-Binding Proteins