Deletion of PI3K-p85α gene impairs lineage commitment, terminal maturation, cytokine generation and cytotoxicity of NK cells

Abstract

Class IA phosphotidylinositol-3-kinases (PI3Ks) are a family of p85/p110 heterodimeric lipid kinases that are important in regulating signaling events in B and T cells. However, their role in natural killer (NK) cells is not understood. Here, using mice that lack the regulatory p85a subunit and its alternatively spliced variants p55a/p50a (collectively termed as p85a À/À ), we defined the role of PI3K in NK cell development and function. p85a À/À mice had impaired lineage commitment leading to reduced NK cellularity in the bone marrow and liver. p85a À/À NK cells showed a defective Ly49 subset specification and a decreased expression of CD43. Lack of p85a severely reduced the NK-mediated cytotoxicity against tumor cells representing 'induced-self' and 'missing-self'. More importantly, NKG2D and NK1.1 receptor-mediated cytokine and chemokine generation was significantly compromised in p85a À/À NK cells. These results reveal a previously unrecognized role of p85a in the development, terminal maturation, cytokine/chemokine generation and tumor clearance of NK cells.

A Targeted siRNA Screen Identifies Regulators of Cdc42 Activity at the Natural Killer Cell Immunological Synapse

“…In PC12 cells monitored with various Previous work has implicated p85a in NK cell function. Mouse p85a knockout NK cells have reduced cytotoxic activity and cytokine production compared to those of wild-type NK cells (59), although a direct link between p85a and Cdc42 activity has not been demonstrated. p85a acts downstream of NKG2D activation by inhibiting the Crk-like protein CrkL, which reduces the extent of MTOC reorientation and cytotoxicity (60); however, NKG2D is not found on YTS NK cells (61), so it seems likely that another upstream signaling pathway is involved.…”

NK cell-based approach for screening novel functional immune genes

“…The NKG2D/DAP10 signaling pathways have been proved to play important roles in the cytotoxicity of NK cells [15][16][17]. To investigate this signaling pathway and clarify the effect of candidate genes on NK-92 cells, NK-92-vector cells and NK-92-Gene1 cells were activated with anti-NKG2D mAb.…”

p85α is an intrinsic regulator of human natural killer cell effector functions

“…3 Although human NK-cell maturation was not perturbed, we decided, on the basis of animal model data, 3 to investigate the functional consequences of the PIK3R1 mutation in human NK-cell biology. Baseline degranulation against the human erythroleukemia cell line K562, measured as CD107a expression of resting NK cells, was similar between healthy controls and patients: 15% (healthy donor [HD]) versus 14% (patient 1) and 6% (patient 2) (Fig 1, A, upper panel, and B).…”

“…This impairment was also confirmed with the cytotoxic chrome release assay (Fig 1, C), underscoring an important role for p85a in this process in humans, similar to what was observed in the p85a knockout mice. 3 We then investigated whether IFN-g production, a prominent biological feature of NK cells, was affected by the presence of the p85a-dominant activating mutant. We thus evaluated IFN-g production by patients' and healthy controls' NK cells before and after simultaneous stimulation with IL-12 and IL-18.…”