Schurich Anna, Böttcher Jan P, Burgdorf Sven, Penzler Patrick, Hegenbarth Silke, Kern Michaela, Dolf Andreas, Endl Elmar, Schultze Joachim, Wiertz Emmanuel, Stabenow Dirk, Kurts Christian, Knolle Percy
Institute of Molecular Medicine and Experimental Immunology, University Hospital Bonn, Bonn, Germany.
Hepatology. 2009 Sep;50(3):909-19. doi: 10.1002/hep.23075.
Cross-presentation is an important function of immune competent cells, such as dendritic cells (DCs), macrophages, and an organ-resident liver cell population, i.e., liver sinusoidal endothelial cells (LSECs). Here, we characterize in direct comparison to DCs the distinct dynamics and kinetics of cross-presentation employed by LSECs, which promote tolerance induction in CD8 T cells. We found that LSECs were as competent in cross-presenting circulating soluble antigen ex vivo as DCs at a per-cell basis. However, antigen uptake in vivo was 100-fold more pronounced in LSECs, indicating distinct mechanisms of cross-presentation. In contrast to mannose-receptor-mediated antigen uptake and routing into stable endosomes dedicated to cross-presentation in DCs, we observed distinct antigen-uptake and endosomal routing with high antigen turnover in LSECs that resulted in short-lived cross-presentation. Receptor-mediated endocytosis did not always lead to cross-presentation, because immune-complexed antigen taken up by the Fc-receptor was not cross-presented by LSECs, indicating that induction of CD8 T cell tolerance by LSECs is impaired in the presence of preexisting immunity.
These results provide a mechanistic explanation how organ-resident LSECs accommodate continuous scavenger function with the capacity to cross-present circulating antigens using distinct kinetics and dynamics of antigen-uptake, routing and cross-presentation compared to DCs.
交叉呈递是免疫活性细胞的一项重要功能，如树突状细胞（DCs）、巨噬细胞以及一种驻留于器官的肝细胞群体，即肝窦内皮细胞（LSECs）。在此，我们通过与DCs直接比较，对LSECs所采用的促进CD8 T细胞耐受诱导的交叉呈递的独特动态和动力学进行了表征。我们发现，在体外每细胞基础上，LSECs在交叉呈递循环可溶性抗原方面与DCs一样有能力。然而，LSECs在体内的抗原摄取比DCs明显高100倍，表明交叉呈递的机制不同。与甘露糖受体介导的抗原摄取以及在DCs中进入专门用于交叉呈递的稳定内体的途径不同，我们观察到LSECs中有独特的抗原摄取和内体途径，抗原周转快，导致交叉呈递短暂。受体介导的内吞作用并不总是导致交叉呈递，因为通过Fc受体摄取的免疫复合物抗原不会被LSECs交叉呈递，这表明在已有免疫存在的情况下，LSECs对CD8 T细胞耐受的诱导会受损。
这些结果提供了一种机制性解释，即驻留于器官的LSECs如何通过与DCs不同的抗原摄取、转运和交叉呈递的动力学和动态来兼顾持续的清除功能和交叉呈递循环抗原的能力。
