Trafficking and activation of murine natural killer cells: Differing roles for IFN-γ and IL-2

Abstract

The repeated ip injection of highly purified recombinant IFN-γ or IL-2 resulted in a local increase in peritoneal NK activity. This increase in lytic activity was paralleled by increases in the number of peritoneal leukocytes reacting with a rat monoclonal antibody directed against the NK cell-associated surface antigen LGL-1. LGL-1 reacts specifically with the majority of murine NK cells in BALB/c and C57BL/6 mice. A single injection of IFN-γ induced more peritoneal NK activity at 24 hr than IL-2 on a protein basis. Both cytokines induced increases in the number of LGL-1 + peritoneal cells by 24 hr after injection. Simultaneous injection of suboptimal amounts of IFN-γ (100 U) and IL-2 (10,000 U) resulted in a significant augmentation of peritoneal NK activity over that observed with either cytokine alone. Also, the peritoneal NK activity generated in response to ip injection of high doses of IL-2 (100,000 U) could be dramatically reduced by simultaneous injection of a neutralizing monoclonal antibody to IFN-γ. Administration of IFN-γ 1 day prior to IL-2 resulted in a significant augmentation of the NK activity above that observed with the individual cytokines. In contrast, injection of IL-2 prior to IFN-γ did not enhance NK activity over that observed with the individual cytokines. Both cytokines must be injected ip for the complementary effects of IFN-γ and IL-2 on peritoneal NK activity to occur. In contrast, in vitro incubation of peritoneal leukocytes with IFN-γ resulted in neither a significant enhancement of NK lytic activity nor an increase in the number of LGL-1 + cells. In vitro treatment of peritoneal leukocytes with IL-2 always resulted in significant augmentation of NK lytic activity in the absence of any increase in the number of LGL-1 + cells. These data are consistent with the hypothesis that the local release of IFN-γ increases peritoneal NK activity by promoting the influx of blood-borne LGL-1 + NK cells from other sites. In contrast, low doses of IL-2 augment the lytic activity of local resident NK cells, whereas high doses of this cytokine induce both an activation of local NK cells and emigration of LGL-1 + NK cells from other sites due to the endogenous generation of IFN-γ within the peritoneal cavity. Therefore, the local release of IFN-γ may play an important role in regulating NK cell infiltration in vivo.