Department of Medicine and Surgery, Liver Center and Transplantation Institute, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
Hepatology. 2010 May;51(5):1702-11. doi: 10.1002/hep.23510.
Natural killer (NK) cells play crucial roles in innate immunity and express CD39 (Ecto-nucleoside triphosphate diphosphohydrolase 1 [E-NTPD1]), a rate-limiting ectonucleotidase in the phosphohydrolysis of extracellular nucleotides to adenosine. We have studied the effects of CD39 gene deletion on NK cells in dictating outcomes after partial hepatic ischemia/reperfusion injury (IRI). We show in mice that gene deletion of CD39 is associated with marked decreases in phosphohydrolysis of adenosine triphosphate (ATP) and adenosine diphosphate to adenosine monophosphate on NK cells, thereby modulating the type-2 purinergic (P2) receptors demonstrated on these cells. We note that CD39-null mice are protected from acute vascular injury after single-lobe warm IRI, and, relative to control wild-type mice, display significantly less elevation of aminotransferases with less pronounced histopathological changes associated with IRI. Selective adoptive transfers of immune cells into Rag2/common gamma null mice (deficient in T cells, B cells, and NK/NKT cells) suggest that it is CD39 deletion on NK cells that provides end-organ protection, which is comparable to that seen in the absence of interferon gamma. Indeed, NK effector mechanisms such as interferon gamma secretion are inhibited by P2 receptor activation in vitro. Specifically, ATPgammaS (a nonhydrolyzable ATP analog) inhibits secretion of interferon gamma by NK cells in response to interleukin-12 and interleukin-18, providing a mechanistic link between CD39 deletion and altered cytokine secretion.
We propose that CD39 deficiency and changes in P2 receptor activation abrogate secretion of interferon gamma by NK cells in response to inflammatory mediators, thereby limiting tissue damage mediated by these innate immune cells during IRI.
自然杀伤 (NK) 细胞在先天免疫中发挥着至关重要的作用，并表达 CD39（外核苷酸三磷酸二磷酸水解酶 1 [E-NTPD1]），这是细胞外核苷酸磷酸水解为腺苷的限速外核苷酸酶。我们研究了 CD39 基因缺失对 NK 细胞在部分肝缺血/再灌注损伤 (IRI) 后结果的影响。我们在小鼠中表明，CD39 基因缺失与 NK 细胞中三磷酸腺苷 (ATP) 和二磷酸腺苷向单磷酸腺苷的磷酸水解明显减少有关，从而调节这些细胞上显示的 2 型嘌呤能 (P2) 受体。我们注意到，CD39 缺失小鼠在单叶温热 IRI 后免受急性血管损伤，与对照野生型小鼠相比，氨基转移酶升高幅度较小，与 IRI 相关的组织病理学变化不明显。将免疫细胞选择性过继转移到 Rag2/共同γ 缺失小鼠（缺乏 T 细胞、B 细胞和 NK/NKT 细胞）中表明，是 NK 细胞上的 CD39 缺失提供了终末器官保护，与干扰素 γ 缺失时所见相当。事实上，P2 受体激活在体外抑制 NK 效应器机制，如干扰素 γ 的分泌。具体而言，ATPγS（一种不可水解的 ATP 类似物）抑制 NK 细胞对白细胞介素 12 和白细胞介素 18 的反应中干扰素 γ 的分泌，为 CD39 缺失和改变细胞因子分泌之间提供了机制联系。
我们提出，CD39 缺乏和 P2 受体激活的变化阻止了 NK 细胞对炎症介质的干扰素 γ 分泌，从而限制了这些先天免疫细胞在 IRI 期间介导的组织损伤。
