title: Phosphatidylinositol-3-kinase activity during in vitro dendritic cell generation determines suppressive or stimulatory capacity.
abstract: Modulating PI3K at different stages of dendritic cells (DC) generation could be a novel means to balance the generation of immunosuppressive versus immunostimulatory DC. We show that PI3K inhibition during mouse DC generation in vitro results in cells that are potently immunosuppressive and characteristic of CD8alpha- CD11c+ CD11b+ DC. These DC exhibited low surface class I and class II MHC, CD40, and CD86 and did not produce TNF-alpha. In allogeneic MLR, these DC were suppressive. Although in these mixed cultures, there was no increase in the frequency of CD4+ CD25+ Foxp3+ cells, the Foxp3 content on a per cell basis was significantly increased. Sustained TLR9 signaling in the presence of PI3K inhibition during DC generation overrode the cells' suppressive phenotype.
authors.affiliation: Department of Pediatrics, Division of Immunogenetics, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, 4401 Penn Avenue, Pittsburgh, PA 15224, USA.
authors.forename: Valentina
authors.initials: V
authors.lastname: Di Caro
authors.forename: Antonella
authors.initials: A
authors.lastname: D'Anneo
authors.forename: Brett
authors.initials: B
authors.lastname: Phillips
authors.forename: Carl
authors.initials: C
authors.lastname: Engman
authors.forename: Jo
authors.initials: J
authors.lastname: Harnaha
authors.forename: Massimo
authors.initials: M
authors.lastname: Trucco
authors.forename: Nick
authors.initials: N
authors.lastname: Giannoukakis
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D039521:CD11c Antigen / Q000378:metabolism; D002867:Chromones / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology; D007155:Immunologic Factors / Q000494:pharmacology; D007165:Immunosuppression Therapy; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009025:Morpholines / Q000494:pharmacology; D009841:Oligonucleotides / Q000494:pharmacology; D010641:Phenotype; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000819:agonists / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D039521:CD11c Antigen; D002867:Chromones; D016207:Cytokines; D007155:Immunologic Factors; D009025:Morpholines; D009841:Oligonucleotides; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051217:Toll-Like Receptor 9; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D058539:Phosphatidylinositol 3-Kinase; D017346:Protein Serine-Threonine Kinases