INTERLEUKIN-12 AND TUMOR-NECROSIS-FACTOR-ALPHA ARE COSTIMULATORS OF INTERFERON-GAMMA PRODUCTION BY NATURAL-KILLER-CELLS IN SEVERE COMBINED IMMUNODEFICIENCY MICE WITH LISTERIOSIS, AND INTERLEUKIN-10 IS A PHYSIOLOGICAL ANTAGONIST

Listeriosis in mice with the severe combined immunodeficiency (SCID) m utation is an established model in vivo and in vitro of interferon gam ma (IFN-gamma)-dependent macrophage activation by natural killer (NK) cells during the development of natural immunity. We demonstrate that IFN-gamma production from SCID splenocytes is stimulated by interleuki n (IL) 12, tumor necrosis factor alpha (TNF-alpha), and IL-2 but is in hibited by IL-10. IL-10, IL-12, and TNF are induced by heat-killed Lis teria monocytogenes (hk-LM) from SCID splenocytes and peritoneal macro phages. IL-12 production is necessary for hk-LM to stimulate IFN-gamma production by SCID splenocytes since neutralization of IL-12 totally blocks IFN-gamma production in this system. TNF-alpha and IL-2 act syn ergistically with IL-12 to augment IFN-gamma production. Also, exogeno us IL-2 increases the response of NK cells to hk-LM or to IL-12 and TN F-alpha. In contrast, IL-10 inhibits hk-LM-induced IFN-gamma productio n at two levels: (i) by inhibiting TNF and IL-12 production from these cultures (presumably from the macrophage) and (ii) by inhibiting the stimulatory effects of IL-12 and TNF-alpha on NK-cell IFN-gamma produc tion. Thus, these data indicate that macrophage production of TNF-alph a and IL-12 stimulates the release of IFN-gamma by NK cells and that I L-10 produced in response to hk-LM inhibits this response at the level of the macrophage and the NK cell.