PI3K activity in dendritic cells exerts paradoxical effects during autoimmune inflammation. (July 2019)

• Record Type: Journal Article
• Authors: Datler, Hannes; Vogel, Andrea; Kerndl, Martina; Baumgartinger, Christina; Musiejovsky, Laszlo; Makivic, Nina; Frech, Sophie; Niederreiter, Birgit; Haider, Thomas; Pühringer, Marlene; Brunner, Julia Stefanie; Sharif, Omar; Schabbauer, Gernot
• Is Part Of: Molecular immunology. Volume 111(2019:Jul.)
• Page Start: 32
• Page End: 42
• Publication Date: 2019-07
• Subjects: anti-IFN-γ functional blocking antibody against IFN-γ -- AKT protein kinase B -- APC professional antigen presenting cell -- BM-DC bone marrow derived dendritic cell -- CFA complete freud's adjuvant -- CNS central nervous system -- dLN inguinal draining lymph node -- EAE experimental autoimmune encephalitis -- GM-CSF granulocyte-macrophage colony-stimulating factor -- gp61 lymphocytic choriomeningitis virus peptide (position 61–80) -- GSK3β glycogen synthase kinase 3β -- H&E hematoxylin and eosin staining -- IFN-γ Interferonү -- IL interleukin -- LCMV lymphocytic choriomeningitis virus -- moDC monocyte derived dendritic cell -- MOG35-55 myelin-oligodendrocyte-glycoprotein peptide (position 35–55) -- moMO monocyte derived macrophage -- MS multiple sclerosis -- OVA ovalbumin (chicken) -- p38 MAP-kinase -- p85α regulatory subunit p85α -- PAMPs pathogen associated molecular patterns PI3K: phosphoinositol-3-kinase -- PIP3 phosphoinositol-3-phosphate -- PTEN phosphatase and tensin homolog -- PTX pertussis toxin -- RORγT RAR-related orphan receptor gamma T -- TGF-β transforming growth factor β -- TH T helper cell -- TH1 effector T helper cell type 1 -- TH17 effector T helper cell type 17 -- T-bet T-Cell-Specific T-Box Transcription Factor -- T-reg regulatory T helper cell; PI3K -- p85α regulatory subunit -- EAE -- TH1 -- TH17 -- IFN-γ; Immunochemistry -- Periodicals; Molecular biology -- Periodicals; Immunochemistry -- Periodicals; Allergy and Immunology -- Periodicals; Molecular Biology -- Periodicals; Immunochimie -- Périodiques; Biologie moléculaire -- Périodiques; Immunochemistry; Molecular biology; Periodicals; Electronic journals; 571.96
• DOI: 10.1016/j.molimm.2019.03.015
• Languages: English
• ISSNs: 0161-5890

Abstract

Highlights: Dendritic cell (DC) expressed PI3K restrains cytokine secretion and antigen presentation. DC expressed PI3K dampens EAE associated TH 1 and TH 17 responses. PI3K activity in DCs but not macrophages or neutrophils worsens autoimmunity. Detrimental effects of DC expressed PI3K in EAE are dependent on IFN-γ. Abstract: The peripheral activation of autoreactive T cells and subsequent central nervous system (CNS) immune cell infiltration are key events relevant for experimental autoimmune encephalomyelitis (EAE), a commonly employed multiple sclerosis (MS) model, influenced by TH 1 and TH 17 mediated immunity. The phosphoinositide-3-kinase (PI3K)-AKT kinase pathway modulates outcome during EAE, with direct actions of PI3K on adaptive immunity implicated in deleterious and effects on antigen presenting cells involved in beneficial responses during EAE. Here, by genetically deleting the regulatory subunit of Class Ia PI3K, p85α, in selective myeloid cells, we aimed to resolve the impact of PI3K in EAE. While genetically deleting PI3K in LysM expressing cells exerted unremarkable effects, attenuating PI3K function in CD11c + dendritic cells (DCs), promoted secretion of pathogenic EAE promoting cytokines, particularly skewing TH 1 and TH 17 immunity, while notably, improving health in EAE. Neutralizing IFN-γ activity using blocking antibodies revealed a prolonged TH 1 response was critical for the decreased disease of these animals. Thus, PI3K-AKT signaling in DCs acts in a paradoxical manner. While attenuating EAE associated TH 1 and TH 17 responses, it impairs health during autoimmune inflammation.