title: Loss of Phosphatase and Tensin Homolog in APCs Impedes Th17-Mediated Autoimmune Encephalomyelitis.
abstract: The PI3K signaling cascade in APCs has been recognized as an essential pathway to initiate, maintain, and resolve immune responses. In this study, we demonstrate that a cell type-specific loss of the PI3K antagonist phosphatase and tensin homolog (PTEN) in myeloid cells renders APCs toward a regulatory phenotype. APCs deficient for PTEN exhibit reduced activation of p38 MAPK and reduced expression of T cell-polarizing cytokines. Furthermore, PTEN deficiency leads to upregulation of markers for alternative activation, such as Arginase 1, with concomitant downregulation of inducible NO synthase in APCs in vitro and in vivo. As a result, T cell polarization was dysfunctional in PTEN(-/-) APCs, in particular affecting the Th17 cell subset. Intriguingly, mice with cell type-specific deletions of PTEN-targeting APCs were protected from experimental autoimmune encephalomyelitis, which was accompanied by a pronounced reduction of IL-17- and IL-22-producing autoreactive T cells and reduced CNS influx of classically activated monocytes/macrophages. These observations support the notion that activation of the PI3K signaling cascade promotes regulatory APC properties and suppresses pathogenic T cell polarization, thereby reducing the clinical symptoms and pathology of experimental autoimmune encephalomyelitis.
authors.affiliation: Institute for Physiology, Center for Physiology and Pharmacology, Medical University of Vienna, A-1090 Vienna, Austria;
authors.forename: Emine
authors.initials: E
authors.lastname: Sahin
authors.affiliation: Institute for Physiology, Center for Physiology and Pharmacology, Medical University of Vienna, A-1090 Vienna, Austria;
authors.forename: Julia S
authors.initials: JS
authors.lastname: Brunner
authors.affiliation: Institute for Physiology, Center for Physiology and Pharmacology, Medical University of Vienna, A-1090 Vienna, Austria;
authors.forename: Julia B
authors.initials: JB
authors.lastname: Kral
authors.affiliation: Institute for Physiology, Center for Physiology and Pharmacology, Medical University of Vienna, A-1090 Vienna, Austria;
authors.forename: Mario
authors.initials: M
authors.lastname: Kuttke
authors.affiliation: Institute for Physiology, Center for Physiology and Pharmacology, Medical University of Vienna, A-1090 Vienna, Austria;
authors.forename: Leslie
authors.initials: L
authors.lastname: Hanzl
authors.affiliation: Institute for Physiology, Center for Physiology and Pharmacology, Medical University of Vienna, A-1090 Vienna, Austria;
authors.forename: Hannes
authors.initials: H
authors.lastname: Datler
authors.affiliation: Institute for Physiology, Center for Physiology and Pharmacology, Medical University of Vienna, A-1090 Vienna, Austria;
authors.forename: Hannah
authors.initials: H
authors.lastname: Paar
authors.affiliation: Institute for Physiology, Center for Physiology and Pharmacology, Medical University of Vienna, A-1090 Vienna, Austria;
authors.forename: Nick
authors.initials: N
authors.lastname: Neuwinger
authors.affiliation: Division of Rheumatology, Internal Medicine III, Medical University of Vienna, A-1090 Vienna, Austria;
authors.forename: Victoria
authors.initials: V
authors.lastname: Saferding
authors.affiliation: Department of Immune Modulation, Department of Dermatology, University Hospital Erlangen, 91052 Erlangen, Germany;
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Zinser
authors.affiliation: St. Anna Children's Cancer Research Institute, A-1090 Vienna, Austria;
authors.forename: Angela
authors.initials: A
authors.lastname: Halfmann
authors.affiliation: St. Anna Children's Cancer Research Institute, A-1090 Vienna, Austria;
authors.forename: Klara
authors.initials: K
authors.lastname: Soukup
authors.affiliation: Institute for Physiology, Center for Physiology and Pharmacology, Medical University of Vienna, A-1090 Vienna, Austria;
authors.forename: Eva
authors.initials: E
authors.lastname: Hainzl
authors.affiliation: Institute for Physiology, Center for Physiology and Pharmacology, Medical University of Vienna, A-1090 Vienna, Austria;
authors.forename: Tobias
authors.initials: T
authors.lastname: Lohmeyer
authors.affiliation: Division of Rheumatology, Internal Medicine III, Medical University of Vienna, A-1090 Vienna, Austria;
authors.forename: Birgit
authors.initials: B
authors.lastname: Niederreiter
authors.affiliation: University Clinic for Trauma Surgery, Medical University of Vienna, A-1090 Vienna, Austria;
authors.forename: Thomas
authors.initials: T
authors.lastname: Haider
authors.affiliation: St. Anna Children's Cancer Research Institute, A-1090 Vienna, Austria;
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Dohnal
authors.affiliation: Department of Internal Medicine 3, University Hospital Erlangen, 91052 Erlangen, Germany; Institute for Clinical Immunology, University Hospital Erlangen, 91052 Erlangen, Germany; and Nikolaus Fiebiger Center of Molecular Medicine, University Hospital Erlangen, University of Erlangen-Nuremberg, 91052 Erlangen, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Krönke
authors.affiliation: Division of Rheumatology, Internal Medicine III, Medical University of Vienna, A-1090 Vienna, Austria; gernot.schabbauer@meduniwien.ac.at stephan.blueml@meduniwien.ac.at.
authors.forename: Stephan
authors.initials: S
authors.lastname: Blüml
authors.affiliation: Institute for Physiology, Center for Physiology and Pharmacology, Medical University of Vienna, A-1090 Vienna, Austria; gernot.schabbauer@meduniwien.ac.at stephan.blueml@meduniwien.ac.at.
authors.forename: Gernot
authors.initials: G
authors.lastname: Schabbauer
mesh_terms: D000818:Animals; D001119:Arginase / Q000096:biosynthesis; D015551:Autoimmunity / Q000276:immunology; D039521:CD11c Antigen / Q000096:biosynthesis; D002454:Cell Differentiation / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics* / Q000276:immunology* / Q000517:prevention & control; D004789:Enzyme Activation / Q000235:genetics / Q000276:immunology; D020381:Interleukin-17 / Q000096:biosynthesis; D007378:Interleukins / Q000096:biosynthesis; D008213:Lymphocyte Activation; D008262:Macrophage Activation / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000276:immunology; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D010446:Peptide Fragments / Q000276:immunology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000276:immunology; D000097043:Interleukin-22
chemical_list: D001119:Arginase; D039521:CD11c Antigen; D020381:Interleukin-17; D007378:Interleukins; D063308:Myelin-Oligodendrocyte Glycoprotein; D052247:Nitric Oxide Synthase Type II; D051059:PTEN Phosphohydrolase; D010446:Peptide Fragments; D019869:Phosphatidylinositol 3-Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D000097043:Interleukin-22; C445081:myelin oligodendrocyte glycoprotein (35-55); C487757:Pten protein, mouse; C544448:Arg1 protein, mouse