Beirne B. Carter Center for Immunology Research, Department ofMicrobiology, University of Virginia, Charlottesville, VA 22908, USA.
J Immunol. 2010 Mar 1;184(5):2693-701. doi: 10.4049/jimmunol.0901362. Epub 2010 Feb 1.
The tolerogenic nature of the liver allows daily exposure to gut-derived foreign Ags without causing inflammation, but it may facilitate persistent infection in the liver. NK cells play a central role in innate immunity, as well as in shaping the adaptive immune response. We hypothesized that the naive mouse liver maintains intrahepatic NK cells in a functionally hyporesponsive state. Compared with splenic NK cells, liver NK cells displayed a dampened IFN-gamma response to IL-12/IL-18 stimulation. Importantly, the liver contains a significant population of functionally hyporesponsive NK cells that express high levels of the inhibitory receptor NKG2A and lack expression of MHC class I-binding Ly49 receptors. Adoptively transferred splenic NK cells that migrate to the liver displayed phenotypic and functional changes, suggesting that the liver environment modifies NK cell receptor expression and functional responsiveness. Notably, IL-10 is present at high levels within the liver, and in vivo blockade of IL-10R resulted in a decreased percentage of intrahepatic NKG2A(+)Ly49(-) NK cells. These data suggest that the liver environment regulates NK cell receptor expression and that IL-10 contributes to the regulation of liver NK cells, in part, by maintaining a greater percentage of the hyporesponsive NKG2A(+)Ly49(-) NK cells in the liver.
肝脏的耐受特性允许其每天暴露于源自肠道的外来抗原而不引起炎症，但这可能促进肝脏中的持续感染。NK 细胞在先天免疫以及塑造适应性免疫反应中发挥核心作用。我们假设，幼稚的小鼠肝脏使肝内 NK 细胞保持在功能低反应状态。与脾 NK 细胞相比，肝 NK 细胞对 IL-12/IL-18 刺激的 IFN-γ反应减弱。重要的是，肝脏含有大量功能低反应性的 NK 细胞，这些细胞表达高水平的抑制性受体 NKG2A，缺乏 MHC 类 I 结合的 Ly49 受体表达。转移到肝脏的脾 NK 细胞表现出表型和功能变化，表明肝脏环境改变了 NK 细胞受体表达和功能反应性。值得注意的是，IL-10 在肝脏中含量很高，体内阻断 IL-10R 导致肝内 NKG2A(+)Ly49(-)NK 细胞的百分比降低。这些数据表明，肝脏环境调节 NK 细胞受体表达，IL-10 通过维持肝脏中更多比例的低反应性 NKG2A(+)Ly49(-)NK 细胞，部分参与了肝脏 NK 细胞的调节。
