Differential expression of SHIP1 in CD56bright and CD56dim NK cells provides a molecular basis for distinct functional responses to monokine costimulation

Monocyte cytokines (ie, monokines) induce natural killer (NK) cells to produce interferon-gamma (IFN-gamma), which is critical for monocyte clearance of infectious pathogens and tumor surveillance. Human CD56(bright) NK cells produce far more IFN-gamma in response to monolkines than do CD56(dim) NK cells. The kinases and phosphatases involved in regulating IFN-gamma production by monokine-activated NK cells are not clearly identified. SHIP1 is a 5' inositol phosphatase that dephosphorylates the phosphaticlylinositol-3 kinase (PI-3K) product P13,4,5P3. Here, we show that constitutive expression of SHIP1 is distinctly lower in CD56(bright) NK cells compared with CD56(dim) NK cells, suggesting it could be an important negative regulator of IFN-gamma production in monokineactivated NK cells. Indeed, overexpression of SHIP1 in CD56(bright) NK cells followed by monolkine activation substantially lowered IFN-gamma production. This effect was not seen when NK cells were infected with a SHIP1 mutant containing an inactive catalytic domain. Finally, INK cells in SHIP1(-/-) mice produced more IFN-gamma in response to monokines in vivo than did NK cells from wild-type mice. Collectively, these results demonstrate that SHIP1 negatively regulates monokineinduced NK cell IFN-gamma production in vitro and in vivo and provide the first molecular explanation for an important functional distinction observed between CD56(bright) and CD56(dim) human NK subsets.