Loss of Phosphatase and Tensin Homolog in APCs Impedes Th17-Mediated Autoimmune Encephalomyelitis.

Autor:	Sahin E; Institute for Physiology, Center for Physiology and Pharmacology, Medical University of Vienna, A-1090 Vienna, Austria;, Brunner JS; Institute for Physiology, Center for Physiology and Pharmacology, Medical University of Vienna, A-1090 Vienna, Austria;, Kral JB; Institute for Physiology, Center for Physiology and Pharmacology, Medical University of Vienna, A-1090 Vienna, Austria;, Kuttke M; Institute for Physiology, Center for Physiology and Pharmacology, Medical University of Vienna, A-1090 Vienna, Austria;, Hanzl L; Institute for Physiology, Center for Physiology and Pharmacology, Medical University of Vienna, A-1090 Vienna, Austria;, Datler H; Institute for Physiology, Center for Physiology and Pharmacology, Medical University of Vienna, A-1090 Vienna, Austria;, Paar H; Institute for Physiology, Center for Physiology and Pharmacology, Medical University of Vienna, A-1090 Vienna, Austria;, Neuwinger N; Institute for Physiology, Center for Physiology and Pharmacology, Medical University of Vienna, A-1090 Vienna, Austria;, Saferding V; Division of Rheumatology, Internal Medicine III, Medical University of Vienna, A-1090 Vienna, Austria;, Zinser E; Department of Immune Modulation, Department of Dermatology, University Hospital Erlangen, 91052 Erlangen, Germany;, Halfmann A; St. Anna Children's Cancer Research Institute, A-1090 Vienna, Austria;, Soukup K; St. Anna Children's Cancer Research Institute, A-1090 Vienna, Austria;, Hainzl E; Institute for Physiology, Center for Physiology and Pharmacology, Medical University of Vienna, A-1090 Vienna, Austria;, Lohmeyer T; Institute for Physiology, Center for Physiology and Pharmacology, Medical University of Vienna, A-1090 Vienna, Austria;, Niederreiter B; Division of Rheumatology, Internal Medicine III, Medical University of Vienna, A-1090 Vienna, Austria;, Haider T; University Clinic for Trauma Surgery, Medical University of Vienna, A-1090 Vienna, Austria;, Dohnal AM; St. Anna Children's Cancer Research Institute, A-1090 Vienna, Austria;, Krönke G; 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., Blüml S; Division of Rheumatology, Internal Medicine III, Medical University of Vienna, A-1090 Vienna, Austria; gernot.schabbauer@meduniwien.ac.at stephan.blueml@meduniwien.ac.at., Schabbauer G; 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.
Jazyk:	angličtina
Zdroj:	Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2015 Sep 15; Vol. 195 (6), pp. 2560-70. Date of Electronic Publication: 2015 Aug 05.
DOI:	10.4049/jimmunol.1402511
Abstrakt:	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. (Copyright © 2015 by The American Association of Immunologists, Inc.)
Databáze:	MEDLINE
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