The p110delta catalytic isoform of PI3K is a key player in NK-cell development and cytokine secretion

Abstract

The signal transduction pathways that lead activated natural killer (NK) cells to produce cytokines, releases cytotoxic granules, or do both, are not clearly dissected. For example, phosphoinositide 3-kinases (PI3Ks) are key players in the execution of both functions, but the relative contribution of each isoform is unknown. We show here that the catalytic isoform p110␦, not p110␥, was required for interferon-␥ (IFN-␥), tumor necrosis factor-␣ (TNF-␣), and granulocyte macrophage colony-stimulating factor (GM-CSF) secretion, whereas neither was necessary for cytotoxicity. Yet, when both p110␦ and p110␥ isoforms were inactivated by a combination of genetic and biochemical approaches, cytotoxicity was decreased. NK-cell numbers were also affected by the lack of p110␦ but not p110␥ and more severely so in mice lacking both subunits. These results provide genetic evidence that p110␦ is the dominant PI3K isoform for cytokine secretion by NK cells and suggest that PI3Ks cooperate during NK-cell development and cytotoxicity. ( IntroductionCellular cytotoxicity and production of inflammatory cytokines are the 2 main functions of natural killer (NK) cells. Although distinct cell subpopulations can specialize in one function rather than the other, 1-3 most NK cells develop the potential to do both. Multiple signal transduction pathways can activate NK cells, including some that are also involved in B and T lymphocyte stimulations. 4 Some of the pathways are independent of Syk-family kinases and revolve around phosphoinositide 3-kinases (PI3Ks). 5,6 PI3Ks are divided into 3 subclasses on the basis of their structure. Class I PI3Ks, which are the most studied in mammalian cell signaling, are further subdivided in 2 groups. Class IA consists of 5 isoforms of regulatory subunits (p85␣, p50␣, p55␣, p85␤, and p55␥) and 3 isoforms of catalytic subunits (p110␣, p110␤, and p110␦), which can interact in various combinations and are mostly activated downstream of tyrosine kinase-associated receptors for growth factors, antigens, cytokines, and costimulatory molecules. 7 Class IB includes only one regulatory isoform (p101) and one catalytic isoform (p110␥), and they are mostly activated downstream of G-coupled protein receptors. 8 P110␥ and p110␦ are expressed primarily in leukocytes, whereas p110␣ and p110␤ are expressed in all cells. The recruitment and activation of class I PI3Ks take place through adaptor molecules containing PI3K binding motif (YXXM), which interacts with SH2 domains of the regulatory subunits. Activated class I PI3Ks convert phosphatidylinositol-4,5-bisphospate (PIP 2 ) to phosphatidylinositol-3,4,5-trisphospate (PIP 3 ). 9 PIP 3 acts as a binding site for various intracellular molecules containing pleckstrin-homology (PH) domains that mediate crucial downstream effector functions. For example, AKT/PKB, 10 Vav, 11 BTK (Bruton agammaglobulinemia tyrosine kinase), ITK (IL-2-inducible T-cell kinase), 12 and PLC␥ (phospholipase C-␥) contain PH domains. Class II and III PI3Ks regulate vesicle trafficking, 13 but lit...

G-CSF downregulates natural killer cell-mediated cytotoxicity in donors for hematopoietic SCT

“…It was suggested that NK cell-mediated cytotoxicity might be downregulated by G-CSF through the PI3K/Akt and ERK/MAPK signaling molecules, and the PI3K/Akt signaling then decreased expression of cytotoxicity-related molecules, TPI, while the ERK/MAPK signaling may be involved in regulation of other genes, such as cellular adhesion, polarity, development, cytokine production and granule secretion. 27,28 Recently, clinicians have begun to use new agents such as plerixafor (AMD3100) to optimize the mobilization of HSC before transplantation for treatment of hematologic diseases and inborn errors of metabolism. 23,36 Our results may provide additional important information regarding regulation of NK cell activity for developers of potential drugs for advanced stem cell mobilization in HSCT.…”

“…Articles have reported that PI3K links NKG2D-activated signaling pathway in NK cells with cellular adhesion, polarity, development, and cytokine and granule secretion, 27,28 implying that inhibition of the PI3K/Akt The relative values were normalized to the internal glyceraldehyde-3-phosphate dehydrogenase control and were calculated from at least three independent experiments. All results were expressed as mean±s.d.…”

PI3Kδ inhibition reduces TNF secretion and neuroinflammation in a mouse cerebral stroke model

“…We have recently shown that PI3Kd activity regulates post-Golgi transport and secretion of TNF in macrophages 18,19 . PI3Kd is similarly implicated in the release of cytokines from other immune cells [20][21][22][23][24] , and PI3Kd-selective inhibitors have significant anti-inflammatory efficacy [24][25][26] . A dual PI3Kg/d inhibitor has been shown to reduce damage in myocardial infarction 27 .…”

RP105 Engages Phosphatidylinositol 3-Kinase p110δ To Facilitate the Trafficking and Secretion of Cytokines in Macrophages during Mycobacterial Infection

“…In contrast to the ubiquitous expression of PI3K p110a and p110b, the p110d subunit is predominantly found in hematopoietic cells. Besides its fundamental roles in B cell development and functions (25), p110d is implicated as a central regulator of intracellular vesicle trafficking associated with inflammatory cytokine responses in different immune cells such as mast cells (26), NK cells (27), B cells (28,29), and T cells (30). In macrophages, p110d was required for fission of TNF-containing vesicles from the Golgi apparatus and transport to the cell surface upon stimulation with the TLR4 agonist LPS (31).…”