title: PI3K-PKB hyperactivation augments human plasmacytoid dendritic cell development and function.
abstract: Plasmacytoid dendritic cells (pDCs) are considered potential tools or targets for immunotherapy. However, current knowledge concerning methodologies to manipulate their development or function remains limited. Here, we investigated the role of the phosphatidylinositol 3-kinase (PI3K)-protein kinase B (PKB)-mammalian target of rapamycin (mTOR) axis in human pDC development, survival, and function. In vitro pDC generation from human cord blood-derived CD34(+) hematopoietic progenitors was reduced by pharmacologic inhibition of PI3K, PKB, or mTOR activity, and peripheral blood pDCs required PI3K-PKB-mTOR signaling to survive. Accordingly, activity of this pathway in circulating pDCs correlated with their abundance in peripheral blood. Importantly, introduction of constitutively active PKB or pharmacologic inhibition of negative regulator phosphatase and tensin homolog (PTEN) resulted in increased pDC numbers in vitro and in vivo. Furthermore, MHC class II and costimulatory molecule expression, and production of IFN-α and TNF-α, were augmented, which could be explained by enhanced IRF7 and NF-κB activation. Finally, the numerically and functionally impaired pDCs of chronic hepatitis B patients demonstrated reduced PI3K-PKB-mTOR activity. In conclusion, intact PI3K-PKB-mTOR signaling regulates development, survival, and function of human pDCs, and pDC development and functionality can be promoted by PI3K-PKB hyperactivation. Manipulation of this pathway or its downstream targets could be used to improve the generation and function of pDCs to augment immunity.
authors.affiliation: Departments of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: Lianne
authors.initials: L
authors.lastname: van de Laar
authors.forename: Aniek
authors.initials: A
authors.lastname: van den Bosch
authors.forename: André
authors.initials: A
authors.lastname: Boonstra
authors.forename: Rekha S
authors.initials: RS
authors.lastname: Binda
authors.forename: Miranda
authors.initials: M
authors.lastname: Buitenhuis
authors.forename: Harry L A
authors.initials: HL
authors.lastname: Janssen
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Coffer
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Woltman
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000276:immunology; D002470:Cell Survival; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology; D003713:Dendritic Cells / Q000166:cytology* / Q000276:immunology*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000276:immunology; D019694:Hepatitis B, Chronic / Q000276:immunology; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000276:immunology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000276:immunology*
chemical_list: D018952:Antigens, CD34; D016207:Cytokines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases