title: mTORC2 Deficiency in Myeloid Dendritic Cells Enhances Their Allogeneic Th1 and Th17 Stimulatory Ability after TLR4 Ligation In Vitro and In Vivo.
abstract: The mammalian/mechanistic target of rapamycin (mTOR) is a key integrative kinase that functions in two independent complexes, mTOR complex (mTORC) 1 and mTORC2. In contrast to the well-defined role of mTORC1 in dendritic cells (DC), little is known about the function of mTORC2. In this study, to our knowledge, we demonstrate for the first time an enhanced ability of mTORC2-deficient myeloid DC to stimulate and polarize allogeneic T cells. We show that activated bone marrow-derived DC from conditional Rictor(-/-) mice exhibit lower coinhibitory B7-H1 molecule expression independently of the stimulus and enhanced IL-6, TNF-α, IL-12p70, and IL-23 production following TLR4 ligation. Accordingly, TLR4-activated Rictor(-/-) DC display augmented allogeneic T cell stimulatory ability, expanding IFN-γ(+) and IL-17(+), but not IL-10(+) or CD4(+)Foxp3(+) regulatory T cells in vitro. A similar DC profile was obtained by stimulating Dectin-1 (C-type lectin family member) on Rictor(-/-) DC. Using novel CD11c-specific Rictor(-/-) mice, we confirm the alloreactive Th1 and Th17 cell-polarizing ability of endogenous mTORC2-deficient DC after TLR4 ligation in vivo. Furthermore, we demonstrate that proinflammatory cytokines produced by Rictor(-/-) DC after LPS stimulation are key in promoting Th1/Th17 responses. These data establish that mTORC2 activity restrains conventional DC proinflammatory capacity and their ability to polarize T cells following TLR and non-TLR stimulation. Our findings provide new insight into the role of mTORC2 in regulating DC function and may have implications for emerging therapeutic strategies that target mTOR in cancer, infectious diseases, and transplantation.
authors.affiliation: Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261;
authors.forename: Dàlia
authors.initials: D
authors.lastname: Raïch-Regué
authors.affiliation: Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261;
authors.forename: Brian R
authors.initials: BR
authors.lastname: Rosborough
authors.affiliation: Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261;
authors.forename: Alicia R
authors.initials: AR
authors.lastname: Watson
authors.affiliation: Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261; and Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261.
authors.forename: Mandy J
authors.initials: MJ
authors.lastname: McGeachy
authors.affiliation: Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261.
authors.forename: Hēth R
authors.initials: HR
authors.lastname: Turnquist
authors.affiliation: Department of Surgery, Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261 thomsonaw@upmc.edu.
authors.forename: Angus W
authors.initials: AW
authors.lastname: Thomson
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015153:Blotting, Western; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000276:immunology*; D005434:Flow Cytometry; D066298:In Vitro Techniques; D008213:Lymphocyte Activation / Q000276:immunology*; D008297:Male; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000172:deficiency / Q000276:immunology*; D022423:Myeloid Cells / Q000276:immunology; D058570:TOR Serine-Threonine Kinases / Q000172:deficiency / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000276:immunology
chemical_list: D046912:Multiprotein Complexes; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases
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