Furthermore, we ascertained whether this event may involve recogn

Furthermore, we ascertained whether this event may involve recognition of terminally desialyiated glycoproteins on the target cell by way of hepatocyte ASGPR. It has been suggested that activated lymphocytes

express a desialylated form of the CD45 receptor16, 17 and that treatment of lymphocytes with neuraminidase may result in their preferential retention in the liver.19 Thus, we determined hepatocyte cytotoxicity against PHA-activated lymphocytes in the presence or absence of ASF. The results shown in Fig. 4B suggest that hepatocytes can indeed recognize activated lymphocytes through an ASGPR-dependent mechanism that results in target cell death. To confirm that our findings presented in Fig. 3 may be extended to activated lymphocytes, we used as effectors hepatocytes after their transfection Ulixertinib research buy with ASGPR-1–specific or scrambled

siRNA. As illustrated in Fig. 4C, ASGPR-specific gene knockdown significantly reduced the level of hepatocyte-mediated lymphocyte cell death, in comparison with untreated (P <0.0001) or scrambled (P < 0.05) siRNA controls. Taken together, these results demonstrate that hepatocytes can kill activated lymphocytes in vitro in a manner that is at least partially dependent upon target cell recognition mediated by ASGPR. This study investigated whether an hepatocyte-specific receptor, which has been known to facilitate removal of desialylated DAPT glycoproteins, could have a role in hepatocyte-mediated Ribonuclease T1 cytotoxicity. In the course of these investigations, we demonstrate that desialylation of the cell surface glycoproteins enhanced target cell apoptosis by hepatocytes. Furthermore, we provide evidence that disruption of the ASGPR binding activity by inclusion of ASF as a competitive ligand

or by siRNA-facilitated knockdown of ASGPR expression resulted in significantly reduced rates of target cell killing by hepatocytes. Furthermore, this study provides the first experimental evidence that hepatocytes can directly kill activated lymphocytes and links this activity, at least in part, to ASGPR-mediated target cell recognition. Following our recent findings demonstrating that hepatocytes are constitutively capable of killing heterologous target cells in vitro,2-4 it remained unresolved how hepatocytes can recognize cells targeted for killing. CTLs and NK cells are well-known immune effectors that limit the degree of bystander cell killing through the usage of antigen-specific T cell receptors or other cellular receptors that recognize cell targets predestined for elimination. For example, the NKG2D receptor is broadly expressed by NK cells and activated CD8+ T cells and facilitates target cell recognition by way of multiple ligands.21 Other members of the NKG2 family are expressed as heterodimers with CD94 and are recognized for their ability to identify nonclassical MHC molecules.

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