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The PP2A inhibitor SET regulates natural killer cell IFN- production

¹ Department of Molecular Virology, Immunology and Medical Genetics, ² Medical Scientific Program, Integrated Biomedical Graduate Program, College of Medicine and Public Health; ³ Division of Epidemiology, College of Public Health; ⁴ Division of Hematology and Oncology, Department of Internal Medicine; and ⁵ The Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210

CORRESPONDENCE Rossana Trotta: rossana.trotta{at}osumc.edu; OR Michael A. Caligiuri: michael.caligiuri{at}osumc.edu

Monokines (i.e., interleukin [IL]-12, -18, and -15) induce natural killer (NK) cells to produce interferon- (IFN-), which is a critical factor for immune surveillance of cancer and monocyte clearance of infection. We show that SET, which is a potent inhibitor of protein phosphatase type 2A (PP2A) activity, is highly expressed in human CD56^bright NK cells, which produce more IFN- than CD56^dim NK cells. SET was up-regulated upon monokine stimulation of primary human NK cells. Furthermore, ectopic overexpression of SET significantly enhanced IFN- gene expression in monokine-stimulated NK cells. In contrast, RNAi-mediated suppression of SET expression renders NK cells inefficient in producing high levels of IFN- in response to monokine costimulation. Mechanistically, suppression of PP2A activity by SET is important for IFN- gene expression in NK cells. In fact, treatment of primary human NK cells with the PP2A activator 1,9-dideoxy-forskolin, as well as administration of the drug to C57BL/6 mice, significantly reduced NK-dependent IFN- production in response to monokine treatment. Further, SET knockdown or pharmacologic activation of PP2A diminished extracellular signal-regulated kinase 1/2, p65RelA, signal transducer and activator of transduction 4 (STAT4), and STAT5 activity in monokine-stimulated NK cells, potentially contributing to the reduction in IFN- gene expression. Thus, SET expression is essential for suppressing PP2A phosphatase activity that would otherwise limit NK cell antitumoral and/or antiinflammatory functions by impairing NK cell production of IFN-.

M.A. Caligiuri and D. Perrotti contributed equally to this paper.

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