Galectin-9 Functionally Impairs Natural Killer Cells in Humans and Mice
Galectin-9 Functionally Impairs Natural Killer Cells in Humans and Mice
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DOI：
10.1128/jvi.01085-12
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发表时间：
2013-05-01
影响因子：
5.4
通讯作者：
Rosen, Hugo R.
中科院分区：
文献类型：
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作者：
Golden-Mason, Lucy;McMahan, Rachel H.;Rosen, Hugo R.
Galectin-9 是一种多效性免疫调节剂，影响多种细胞类型的先天性和适应性免疫。慢性感染丙型肝炎病毒 (HCV) 或 HIV 的患者循环水平升高。关于通过与 galectin-9 相互作用调节自然杀伤 (NK) 细胞功能的数据有限。我们发现，galectin-9 连接可下调多种免疫激活基因，其中包括 8 个参与 NK 细胞介导的细胞毒性途径的基因，损害淋巴因子激活的杀伤作用，并降低经白细胞介素 12 (IL-12)/IL-15 刺激的产生γ干扰素 (IFN-γ) 的 NK 细胞的比例。我们证明 Galectin-9 诱导的转录和功能变化独立于 Tim-3。与人类的这些结果一致，我们发现小鼠中半乳糖凝集素 9 的遗传缺失与 NK 细胞产生更多的 IFN-γ 和增强脱颗粒有关。我们还表明，在短期（4 天）鼠巨细胞病毒感染的情况下，终末分化的 NK 在半乳糖凝集素 9 敲除小鼠的肝脏中积聚，并且在这种情况下，肝脏 NK 自发地产生显着更多的 IFN-γ。综上所述，我们的结果表明，galectin-9 的参与会损害 NK 细胞的功能，包括细胞毒性和细胞因子的产生。
Galectin-9 is a pleiotropic immune modulator affecting numerous cell types of innate and adaptive immunity. Patients with chronic infection with either hepatitis C virus (HCV) or HIV have elevated circulating levels. Limited data exist on the regulation of natural killer (NK) cell function through interaction with galectin-9. We found that galectin-9 ligation downregulates multiple immune-activating genes, including eight involved in the NK cell-mediated cytotoxicity pathway, impairs lymphokine-activated killing, and decreases the proportion of gamma interferon (IFN-gamma)-producing NK cells that had been stimulated with interleukin-12 (IL-12)/IL-15. We demonstrate that the transcriptional and functional changes induced by galectin-9 are independent of Tim-3. Consistent with these results for humans, we find that the genetic absence of galectin-9 in mice is associated with greater IFN-gamma production by NK cells and enhanced degranulation. We also show that in the setting of a short-term (4-day) murine cytomegalovirus infection, terminally differentiated NKs accumulate in the livers of galectin-9 knockout mice, and that hepatic NKs spontaneously produce significantly more IFN-gamma in this setting. Taken together, our results indicate that galectin-9 engagement impairs the function of NK cells, including cytotoxicity and cytokine production.