Differential expression of SHIP1 in CD56bright and CD56 dim NK cells provides a molecular basis for distinct functional responses to monokine costimulation

Rossana Trotta, Robin Parihar, Jianhua Yu, Brian Becknell, Jeffrey Allard, Jing Wen, Wei Ding, Hsiaoyin Mao, Susheela Tridandapani, William E. Carson, Michael A. Caligiuri

Research output: Contribution to journalArticle

64 Scopus citations

Abstract

Monocyte cytokines (ie, monokines) induce natural killer (NK) cells to produce interferon-γ (IFN-γ), which is critical for monocyte clearance of infectious pathogens and tumor surveillance. Human CD56 bright NK cells produce far more IFN-γ in response to monokines than do CD56dim NK cells. The kinases and phosphatases involved in regulating IFN-γ production by monokine-activated NK cells are not clearly identified. SHIP1 is a 5′ inositol phosphatase that dephosphorylates the phosphatidylinositol-3 kinase (PI-3K) product PI3,4,5P3. Here, we show that constitutive expression of SHIP1 is distinctly lower in CD56 bright NK cells compared with CD56dim NK cells, suggesting it could be an important negative regulator of IFN-γ production in monokine-activated NK cells. Indeed, overexpression of SHIP1 in CD56 bright NK cells followed by monokine activation substantially lowered IFN-γ production. This effect was not seen when NK cells were infected with a SHIP1 mutant containing an inactive catalytic domain. Finally, NK cells in SHIP1-/- mice produced more IFN-γ in response to monokines in vivo than did NK cells from wild-type mice. Collectively, these results demonstrate that SHIP1 negatively regulates monokine-induced NK cell IFN-γ production in vitro and in vivo and provide the first molecular explanation for an important functional distinction observed between CD56bright and CD56dim human NK subsets.

Original languageEnglish (US)
Pages (from-to)3011-3018
Number of pages8
JournalBlood
Volume105
Issue number8
DOIs
StatePublished - Apr 15 2005

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Trotta, R., Parihar, R., Yu, J., Becknell, B., Allard, J., Wen, J., Ding, W., Mao, H., Tridandapani, S., Carson, W. E., & Caligiuri, M. A. (2005). Differential expression of SHIP1 in CD56bright and CD56 dim NK cells provides a molecular basis for distinct functional responses to monokine costimulation. Blood, 105(8), 3011-3018. https://doi.org/10.1182/blood-2004-10-4072