Differential expression of SHIP1 in CD56bright and CD56dim NK cells provides a molecular basis for distinct functional responses to monokine costimulation
Differential expression of SHIP1 in CD56bright and CD56dim NK cells provides a molecular basis for distinct functional responses to monokine costimulation
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DOI：
10.1182/blood-2004-10-4072
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发表时间：
2005-04-15
期刊：
影响因子：
20.3
通讯作者：
Caligiuri, MA
中科院分区：
文献类型：
--
作者：
Trotta, R;Parihar, R;Caligiuri, MA
单核细胞细胞因子（即单核因子）诱导自然杀伤（NK）细胞产生干扰素-γ（IFN-γ），这对于单核细胞清除感染性病原体和肿瘤监测至关重要。人类 CD56(bright) NK 细胞响应单核因子产生的 IFN-γ 比 CD56(dim) NK 细胞多得多。参与调节单核因子激活的 NK 细胞产生 IFN-γ 的激酶和磷酸酶尚不清楚。 SHIP1 是一种 5' 肌醇磷酸酶，可使磷酸肌醇 3 激酶 (PI-3K) 产物 P13,4,5P3 去磷酸化。在这里，我们发现与 CD56(dim) NK 细胞相比，SHIP1 在 CD56(bright) NK 细胞中的组成型表达明显较低，这表明它可能是单核因子激活的 NK 细胞中 IFN-γ 产生的重要负调节因子。事实上，在 CD56(bright) NK 细胞中 SHIP1 过度表达，随后单核因子激活可显着降低 IFN-γ 的产生。当 NK 细胞被含有失活催化结构域的 SHIP1 突变体感染时，没有观察到这种效应。最后，SHIP1(-/-)小鼠中的INK细胞响应体内单核因子产生比野生型小鼠中的NK细胞更多的IFN-γ。总的来说，这些结果表明 SHIP1 在体外和体内负调节单核因子诱导的 NK 细胞 IFN-γ 产生，并为 CD56（bright）和 CD56（dim）人类 NK 亚群之间观察到的重要功能区别提供了第一个分子解释。
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.