The effect of NK cell activation by tumor cells on antigen-specific antibody responses.

In addition to mediating direct cytotoxicity, NK cells can exert regulatory effects on specific immune responses. For example, injection of poly (I:C) can alter specific Ab responses, which is attributable to the production of IFN-gamma by NK cells. To test whether direct activation of NK cells can exert the same effect, we have injected, at the same time as Ag challenge, BCL1-C11 tumor cells, which are highly effective inducers of IFN-gamma production by NK cells. The results show a specific enhancement of the IgG2a response, which does not occur with a tumor (70Z/3) that does not induce IFN-gamma production. This enhancement is NK cell and IL-12 dependent. However, BCL1-C11 cells cannot directly induce IL-12 production in peritoneal exudate cells (PECs). On the other hand, PECs from tumor-treated mice produce IL-12 in response to LPS, suggesting that they are primed in vivo. Furthermore, the IL-12 production is NK cell and IFN-gamma dependent. These results indicate that if tumor cells can directly activate NK cells to produce IFN-gamma, this cytokine initiates an amplification loop by activating macrophages to produce IL-12, which in turn activates NK cells further, resulting in the alteration of the isotype distribution of specific Ab responses. Production of the appropriate Ab isotype should enhance Ab-dependent cellular cytotoxicity against targets mediated by NK cells, implicating their role(s) in the specific immune response as well as the initial nonspecific phase.