engleski

Overexpression of intrahepatic NKT cell increases the cell-mediated cytotoxicity against tumor cell lines

The importance of NKT cells, which express the invariant T cell receptor and markers of NK cells lineage (NK1.1 and IL-2R ) is repeatedly emphasized, but the precise immunological function of these "primitive" lymphocytes is still not well defined. As CD1-restricted cells they interact with glycolipid ligands, heat shock proteins and other "stress" or "danger" signals produced by tumors or injured self cells, transferring important information to the rest of the immune system or directly suppressing the tumor growth. AIMS: 1) To induce the overexpression of hepatic NKT cells in experimental models of: a) normal growth, b) hepatic injury, c) autoimmunity and d) bacterial infection and 2) to test the cytotoxicity of intrahepatic and splenic mononuclear lymphatic cells (MNLC) obtained from these mice against syngeneic cells, and NK and LAK-cells sensitive targets. METHODS: C57BL/6 mice were subjected to 1/3 partial hepatectomy (pHx), common bile duct ligation (CBDL), treatment with streptozotocyn to induce diabetes mellitus, or treatment with bacterial product-peptidoglycan-monomer (PGM) and PGM linked with Zn. Phenotypic analyses and testing of cytotoxicity against syngeneic thymocytes, YAC-1 and P-815 cells were made by the use of flow cytometry and PKH-26 Red 2h cytotoxicity assay. RESULTS: In all experimental models the greatest changes were found in the liver where accumulated NK1.1+ /CD3intermadiate cells, expressing IL-2R and CD69. Furthermore, in all models freshly isolated hepatic and particularly splenic MNLC became markedly cytotoxic to syngeneic thymocytes, as well as to NK and LAK-cells sensitive targets, indicating that various stress-related signals might induce the anti-tumor activity of natural killer cells and cytotoxic lymphocytes though activation of autoreactive hepatic NKT cells. Additional data obtained in perforin knock out and FasL deficient (gld/gld) partially hepatectomized mice showed that lytic pathways might involve perforin and FasL-dependent pathways. CONCLUSIONS: Taken together the data point to the liver, as an important immunoregulatory organ, where local tissue injury, or/and apoptosis of infected and immigrated cells might expose conserved stress-induced self structures, resulting in activation of NKT cells, which subsequently potentiate cytotoxic activities of NK and T cells, performing regulatory function in various reparatory processes, as well as in autoimmune, infectious and tumor conditions.

NKT cells; liver; spleen; partial hepatectomy; peptidoglycan-monomer; autoimmune diabetes mellitus

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