title: PI3-Kinase-γ Has a Distinct and Essential Role in Lung-Specific Dendritic Cell Development.
abstract: Development of dendritic cells (DCs) commences in the bone marrow, from where pre-DCs migrate to peripheral organs to differentiate into mature DCs in situ. However, the factors that regulate organ-specific differentiation to give rise to tissue-specific DC subsets remain unclear. Here we show that the Ras-PI3Kγ-Akt-mTOR signaling axis acted downstream of FLT3L signaling and was required for development of lung CD103(+) DCs and, to a smaller extent, for lung CD11b(+) DCs, but not related DC populations in other non-lymphoid organs. Furthermore, we show that in lymphoid organs such as the spleen, DCs depended on a similar signaling network to respond to FLT3 ligand with overlapping and partially redundant roles for kinases PI3Kγ and PI3Kδ. Thus we identified PI3Kγ as an essential organ-specific regulator of lung DC development and discovered a signaling network regulating tissue-specific DC development mediated by FLT3.
authors.affiliation: Institute of Molecular Health Sciences, Department of Biology, ETH Zurich, 8093 Zurich, Switzerland.
authors.forename: Samuel Philip
authors.initials: SP
authors.lastname: Nobs
authors.affiliation: Institute of Molecular Health Sciences, Department of Biology, ETH Zurich, 8093 Zurich, Switzerland.
authors.forename: Christoph
authors.initials: C
authors.lastname: Schneider
authors.affiliation: Department of Endocrinology, Diabetes and Clinical Nutrition, University Hospital, 8091 Zurich, Switzerland.
authors.forename: Maren Gil
authors.initials: MG
authors.lastname: Dietrich
authors.affiliation: Institute for Immunology, Ludwig-Maximillians-University Munich, 80336 Munich, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Brocker
authors.affiliation: Department of Biomedicine, University Basel, 4058 Basel, Switzerland.
authors.forename: Antonius
authors.initials: A
authors.lastname: Rolink
authors.affiliation: Department of Biomedicine, University Basel, 4058 Basel, Switzerland; Department of Molecular Biotechnology and Health Sciences, University of Torino, Via Nizza 52, 10126 Torino, Italy.
authors.forename: Emilio
authors.initials: E
authors.lastname: Hirsch
authors.affiliation: Institute of Molecular Health Sciences, Department of Biology, ETH Zurich, 8093 Zurich, Switzerland. Electronic address: manfred.kopf@ethz.ch.
authors.forename: Manfred
authors.initials: M
authors.lastname: Kopf
mesh_terms: D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation / Q000502:physiology; D058544:Class Ib Phosphatidylinositol 3-Kinase / Q000172:deficiency / Q000502:physiology*; D003713:Dendritic Cells / Q000145:classification / Q000166:cytology*; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D006706:Homeostasis / Q000276:immunology; D007153:Immunologic Deficiency Syndromes / Q000235:genetics / Q000276:immunology; D008168:Lung / Q000166:cytology / Q000201:enzymology / Q000276:immunology*; D008221:Lymphoid Tissue / Q000166:cytology / Q000201:enzymology; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D008565:Membrane Proteins / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000502:physiology; D009928:Organ Specificity; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000502:physiology; D016283:Proto-Oncogene Proteins p21(ras) / Q000502:physiology; D011828:Radiation Chimera; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases / Q000502:physiology; D051941:fms-Like Tyrosine Kinase 3 / Q000502:physiology*
chemical_list: D006575:Heterocyclic Compounds, 3-Ring; C548887:MK 2206; D008565:Membrane Proteins; D046912:Multiprotein Complexes; D011994:Recombinant Proteins; C084881:flt3 ligand protein; D058544:Class Ib Phosphatidylinositol 3-Kinase; C546764:Pik3cg protein, mouse; C497971:Flt3 protein, mouse; D051941:fms-Like Tyrosine Kinase 3; C514862:Akt1 protein, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D016283:Proto-Oncogene Proteins p21(ras)
keywords: FLT3; PI3Kγ; lung dendritic cells; tissue specificity