Abstract
Natural killer (NK) cells and their crosstalk with other immune cells are important for innate immunity against tumor. To explore the role of the interaction between NK cells and macrophages in the regulation of anti-tumor activities of NK cells, we here demonstrate that poly I:C-treated macrophages increased NK cell-mediated cytotoxicity against target tumor cells in NKG2D-dependent manner. In addition, IL-15, IL-18, and IFN-β secreted by poly I:C-treated macrophages are also involved in NKG2D expression and NK cell activation. Interestingly, the increase in expression of NKG2D ligands on macrophages induced a highly NK cell-mediated cytotoxicity against tumor cells, but not against macrophages themselves. Notably, a high expression level of Qa-1, a NKG2A ligand, on macrophages may contribute to such protection of macrophages from NK cell-mediated killing. Furthermore, Qa-1 or NKG2A knockdown and Qa-1 antibody blockade caused the macrophages to be sensitive to NK cytolysis. These results suggested that macrophages may activate NK cells to attack tumor by NKG2D recognition whereas macrophages protect themselves from NK lysis via preferential expression of Qa-1.
Highlights
Natural killer (NK) cells are an integral component of the innate immune system and are characterized by their strong cytolytic activity against tumors and virus-infected cells
YAC-1 was most sensitive to NK cells isolated from polyribocytidilic acid (poly I):C-treated macrophages (p,0.05 at E:T ration of 5:1 and 25:1, and p,0.01 at E:T ration of 50:1, respectively, compared with that of NK cells isolated from untreated macrophages)
We found that compared with untreated NK cells, exposure to untreated macrophages did not result in an increase of NK cells cytotoxicity against both type of target cells (Fig. 1A)
Summary
Natural killer (NK) cells are an integral component of the innate immune system and are characterized by their strong cytolytic activity against tumors and virus-infected cells. CD94/NKG2A is one of the major inhibitory receptors in mice, and it recognizes the non-classical major histocompatibility complex (MHC) molecules Qa-1 that is expressed by most cell types. The actions of NK cells are thought to be mediated by the complex interactions between inhibitory and activating signals sent by cell surface receptors following ligation. Cytokines, such as interleukin (IL)-2, IL-15, IL-12, IL-18 and IL-21, usually produced by other immune cells, and activated antigenpresenting cells (APCs), play important roles in the regulation of NK cell activity [12,13]
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