Functional role of phosphatidylinositol 3-kinase in direct tumor lysis by human natural killer cells.

Abstract

Cytotoxicity is a key function of natural killer (NK) and T cells; yet the molecular mechanism is unclear. We have biological, biochemical and molecular evidence to demonstrate that phosphatidyl-inositol (PI) 3-kinase is critical for direct NK lysis of tumor cells, via control of intracellular granule movement. Tumor cell engagement rapidly activated PI 3-kinase in NK cells within 5 min, as demonstrated by p85 subunit tyrosine phosphorylation and its ability to generate phosphatidylinositol 3-phosphate, PI(3)P, from PI. Wortmannin and LY294002 effectively inhibited NK cells to lyse 51Cr-labeled tumor cells at the same doses that blocked PI-phosphorylating function in tumor-activated NK cells. Immunostaining demonstrated that tumor engagement for only 5 min mobilized perforin and granzyme B from NK cells unidirectionally towards the target, and prior treatment of NK cells with either PI 3-kinase inhibitor effectively stopped this intracellular polarization. Lastly, ectopic expression of dominant-negative p85 or p110 mutant markedly suppressed NK lytic capacity. These results taken together demonstrate that PI 3-kinase may control NK lytic function via granule polarization towards the contacted target cell.

• Authors: Bin Zhong, Jin Hong Liu, Danielle L Gilvary, Kun Jiang, Masato Kasuga, Connie A Ritchey, Joseph A Trapani, Sheng Wei
• Journal: Immunobiology (Immunobiology) Vol. 205 Issue 1 Pg. 74-94 (Mar 2002) ISSN: 0171-2985 [Print] Netherlands
• PMID: 11999346 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Androstadienes
• Chromones
• Enzyme Inhibitors
• Membrane Glycoproteins
• Morpholines
• Pore Forming Cytotoxic Proteins
• Perforin
• 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
• Phosphatidylinositol 3-Kinases
• GZMB protein, human
• Granzymes
• Serine Endopeptidases
• Wortmannin

Topics

• Androstadienes (pharmacology)
• Cell Communication (immunology)
• Chromones (pharmacology)
• Cytotoxicity, Immunologic (drug effects)
• Enzyme Inhibitors (pharmacology)
• Granzymes
• HL-60 Cells
• Hematologic Neoplasms (immunology, pathology)
• Humans
• Jurkat Cells
• Killer Cells, Natural (enzymology, immunology)
• Leukemia
• Membrane Glycoproteins (biosynthesis)
• Morpholines (pharmacology)
• Perforin
• Phosphatidylinositol 3-Kinases (immunology, metabolism)
• Pore Forming Cytotoxic Proteins
• Serine Endopeptidases (biosynthesis)
• Signal Transduction (drug effects, immunology)
• T-Lymphocyte Subsets (immunology)
• Tumor Cells, Cultured
• Wortmannin