Krueger Peter D, Lassen Matthew G, Qiao Huihong, Hahn Young S
Department of Microbiology, University of Virginia School of Medicine, Charlottesville, 22908, USA.
Crit Rev Immunol. 2011;31(1):43-52. doi: 10.1615/critrevimmunol.v31.i1.40.
NK cells represent a large proportion of the lymphocyte population in the liver and are involved in early innate immunity to pathogen infection. As a result of liver endothelial cell fenestrations, parenchymal cells are not separated by a basal membrane, and thereby pathogen-infected hepatocytes are extensively capable of interacting with innate immune cells including NK cells. In addition, hepatic NK cells interact with surrounding DC and alter their differentiation and function. Recent studies reveal that NK cells exhibit a regulatory function that modulates T cell responses through their interaction with DC and/or direct effect on T cells. Thus, NK cells play a central role, not only in innate immunity, but also in shaping the adaptive immune response. During pathogen infection, there is a remarkable increase of hepatic NK cells, possibly due to the expansion of resident liver NK cells and/or recruitement of NK cells from the blood. The liver microenvironment is believed to modulate hepatic NK cell function through the induction of activating/inhibitory receptor expression and inflammatory cytokine secretion. Particularly, the liver maintains intrahepatic NK cells in a functionally hyporesponsive state compared to splenic NK cells: liver NK cells displayed a dampened IFN-γ response to IL-12/IL-18 stimulation. Notably, 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. Importantly, adoptively transferred splenic NK cells that migrate to the liver displayed phenotypic and functional changes, supporting a view that the liver environment modifies NK cell receptor expression and functional responsiveness. In this article, we will review studies on the regulation of NK cell repertoire and function in the hepatic environment and the impact of liver NK cell immunoregulatory function on influencing adaptive immunity.
自然杀伤细胞（NK细胞）在肝脏淋巴细胞群体中占很大比例，参与对病原体感染的早期固有免疫。由于肝内皮细胞有窗孔，实质细胞未被基膜分隔，因此受病原体感染的肝细胞能够广泛地与包括NK细胞在内的固有免疫细胞相互作用。此外，肝脏NK细胞与周围的树突状细胞（DC）相互作用并改变其分化和功能。最近的研究表明，NK细胞具有调节功能，可通过与DC相互作用和/或直接作用于T细胞来调节T细胞反应。因此，NK细胞不仅在固有免疫中起核心作用，而且在塑造适应性免疫反应中也起核心作用。在病原体感染期间，肝脏NK细胞显著增加，这可能是由于驻留肝脏的NK细胞扩增和/或从血液中招募NK细胞所致。肝脏微环境被认为通过诱导激活/抑制性受体表达和炎性细胞因子分泌来调节肝脏NK细胞功能。特别是，与脾NK细胞相比，肝脏使肝内NK细胞维持在功能反应低下的状态：肝脏NK细胞对IL-12/IL-18刺激的IFN-γ反应减弱。值得注意的是，肝脏含有大量功能反应低下的NK细胞，这些细胞表达高水平的抑制性受体NKG2A，且缺乏与MHC I类结合的Ly49受体表达。重要的是，迁移至肝脏的过继转移脾NK细胞表现出表型和功能变化，这支持了一种观点，即肝脏环境可改变NK细胞受体表达和功能反应性。在本文中，我们将综述关于肝脏环境中NK细胞库和功能调节以及肝脏NK细胞免疫调节功能对影响适应性免疫的研究。
