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-␣ and TNF-␣, were augmented, which could be explained by enhanced IRF7 and NF-B 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. (Blood. 2012; 120(25):4982-4991) IntroductionPlasmacytoid dendritic cells (pDCs) represent a specialized DC subset that is recognized for its unique ability to rapidly produce large amounts of type 1 interferons (IFN-␣␤) on the interaction with viruses or nucleic acids of self or nonself origin. 1 Besides direct antiviral activity through the production of IFN-␣␤, pDCs have been implicated in playing a broader role in immunity. pDC activation results in the production of additional proinflammatory cytokines such as TNF-␣ and IL-6, and it stimulates the expression of MHC class I, MHC class II, and costimulatory molecules. These combined functions enable pDCs to activate T helper cells, cytotoxic T lymphocytes, natural killer cells, and plasma cell differentiation. Moreover, pDC-derived cytokines can act as adjuvants for other DC subsets such as myeloid or conventional DC. In contrast, tolerogenic functions of pDC, including the generation of regulatory T cells, have also been described. Similar to other DC subsets, pDC thus show the dual capability of being able to initiate as well as regulate immunity. [1][2][3] In accordance with their broad role in the regulation of immunity, the possibilities to use pDC as either tools or targets for immunotherapy are being increasingly explored. Activation of dysfunctional tumor-resident pDCs may be achieved by administration of TLR agonists, 4,5 and methods to induce antitumor responses by either targeting antigen to endogeno...

X-Chromosome Complement and Estrogen Receptor Signaling Independently Contribute to the Enhanced TLR7-Mediated IFN-α Production of Plasmacytoid Dendritic Cells from Women

“…8C, 8D). We were unable to detect IFN-a + pDC by intracellular staining in cultures stimulated with R-848 for 5 h (not shown), in agreement with previous works by others (33). By contrast, using influenza virus as a TLR7-dependent ligand, we could detect strong IFN-a production in CD34-derived pDCs by intracellular staining (Fig.…”

Estradiol Promotes Functional Responses in Inflammatory and Steady-State Dendritic Cells through Differential Requirement for Activation Function-1 of Estrogen Receptor α

“…Indeed, the PI3K/PKB signaling pathway can be activated by acute exposure to E2 in vitro in different cell types including endothelial cells and cortical neurons through MISS effects (56)(57)(58), and enhanced PKB activity has been recently shown to augment human pDC development and function (59). The continuous presence of E2 in culture could therefore promote PI3K-PKB activation in developing pDCs (59), thereby enhancing their capacity to respond to subsequent TLR stimulation. Alternatively, the AF-1 region of ERa contains multiple Ser residues that can be phosphorylated by several kinases including PKB and MAPK (60).…”

Synergy between rapamycin and FLT3 ligand enhances plasmacytoid dendritic cell–dependent induction of CD4+CD25+FoxP3+ Treg

“…23 PI3K hyperactivation, through deletion of the negative regulator phosphatase and tensin homolog, causes increased DC proliferation. 24 The serine/threonine kinase protein kinase B (PKB, also known as AKT) regulates multiple biological processes by binding various molecules, one of which is the lipid kinase PI3K. 24 Importantly, mTOR is a pivotal downstream mediator of the PI3K/AKT pathway.…”

“…24 The serine/threonine kinase protein kinase B (PKB, also known as AKT) regulates multiple biological processes by binding various molecules, one of which is the lipid kinase PI3K. 24 Importantly, mTOR is a pivotal downstream mediator of the PI3K/AKT pathway. 25 Rapamycin-induced inhibition of mTOR signaling in DCs is associated with changes in DC generation, expansion, activation, and maturation.…”