title: Mechanistic Target of Rapamycin Complex 1/S6 Kinase 1 Signals Influence T Cell Activation Independently of Ribosomal Protein S6 Phosphorylation.
abstract: Ag-dependent activation of naive T cells induces dramatic changes in cellular metabolism that are essential for cell growth, division, and differentiation. In recent years, the serine/threonine kinase mechanistic target of rapamycin (mTOR) has emerged as a key integrator of signaling pathways that regulate these metabolic processes. However, the role of specific downstream effectors of mTOR function in T cells is poorly understood. Ribosomal protein S6 (rpS6) is an essential component of the ribosome and is inducibly phosphorylated following mTOR activation in eukaryotic cells. In the current work, we addressed the role of phosphorylation of rpS6 as an effector of mTOR function in T cell development, growth, proliferation, and differentiation using knockin and TCR transgenic mice. Surprisingly, we demonstrate that rpS6 phosphorylation is not required for any of these processes either in vitro or in vivo. Indeed, rpS6 knockin mice are completely sensitive to the inhibitory effects of rapamycin and an S6 kinase 1 (S6K1)-specific inhibitor on T cell activation and proliferation. These results place the mTOR complex 1-S6K1 axis as a crucial determinant of T cell activation independently of its ability to regulate rpS6 phosphorylation.
authors.affiliation: Institute of Immunology and Infection Research, Ashworth Laboratories, University of Edinburgh, Edinburgh EH9 3FL, United Kingdom; and.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Salmond
authors.affiliation: Institute of Immunology and Infection Research, Ashworth Laboratories, University of Edinburgh, Edinburgh EH9 3FL, United Kingdom; and.
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Brownlie
authors.affiliation: Department of Biochemistry and Molecular Biology, Institute for Medical Research Israel-Canada, The Hebrew University Hadassah Medical School, 91120 Jerusalem, Israel.
authors.forename: Oded
authors.initials: O
authors.lastname: Meyuhas
authors.affiliation: Institute of Immunology and Infection Research, Ashworth Laboratories, University of Edinburgh, Edinburgh EH9 3FL, United Kingdom; and rose.zamoyska@ed.ac.uk.
authors.forename: Rose
authors.initials: R
authors.lastname: Zamoyska
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000235:genetics; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D008213:Lymphocyte Activation / Q000276:immunology*; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000378:metabolism*; D010766:Phosphorylation; D038601:Ribosomal Protein S6 / Q000378:metabolism*; D019893:Ribosomal Protein S6 Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology; D020123:Sirolimus / Q000494:pharmacology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D046912:Multiprotein Complexes; D038601:Ribosomal Protein S6; C448579:ribosomal protein S6, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus