Production of gamma interferon by natural killer cells from Toxoplasma gondii-infected SCID mice: regulation by interleukin-10, interleukin-12, and tumor necrosis factor alpha

Abstract

Previous studies of mice have implicated natural killer (NK) cells as mediators of protective activity against Toxoplasma gondii through their production of gamma interferon (IFN-y). In the present study, we have compared NK-cell activity in infected and uninfected SCID mice. Our data reveal that infection results in increased levels of IFN-y in serum and elevated NK-cell activity but that these NK cells were not cytotoxic for T. gondii-infected P815 cells. Treatment with anti-IFN-y antibody abrogated the increase in NK-cell activity and resulted in earlier mortality of infected mice. In vivo treatment with anti-asialo GM1 antiserum reduced NK cell activity and levels of IFN-y in serum but did not alter time to death. Spleen cells from infected mice produced higher levels of IFN-y than those from uninfected mice when stimulated in vitro with live T. gondii or parasite antigen preparations. Further analysis revealed that interleukin 10 (IL-10) inhibited, whereas tumor necrosis factor alpha (TNF-a) and IL-12 enhanced, IFN-y production by spleen cells from infected or uninfected mice. The combination of IL-12 and TNF-a induced higher levels of IFN-y from whole spleen cells of infected mice than from those of uninfected mice. Depletion of the adherent cell population from the spleen cells of infected mice led to a significant reduction in the levels of IFN-.y produced after stimulation with IL-12 plus TNF-at. Similar results did not occur with cells from uninfected mice. These data indicate that other cytokines produced by the adherent cell population from infected mice may be involved in maximal production of IFN-,y by NK cells stimulated with IL-12 and TNF-ce. To assess the importance of endogenous IL-12, a polyclonal anti-IL-12 was administered to infected SCID mice. This treatment led to earlier mortality, indicating that endogenous IL-12 mediates resistance to T. gondii.

Contribution of tumour necrosis factor-alpha (TNF-α) in host defence mechanism against Cryptococcus neoformans

“…This process leads to the accumulation of inflammatory cells, including mononuclear cells. Furthermore, TNFpotentiates the production of IFN-by NK cells in cooperation with IL-12 [15] and enhances the activation of T cells [45]. These biological activities of TNFmight be involved in its protective effect in cryptococcosis.…”

“…TNFacts by activating polymorphonuclear leucocytes and macrophages to augment their antimicrobial potentials and triggers respiratory burst-and nitric oxide (NO)-dependent killing pathways [13,14]. Other studies have also demonstrated that TNFstimulates natural killer (NK) cells in cooperation with IL-12 to produce interferon-gamma (IFN-) [15], which plays an important role in early host defence mechanisms [16] and differentiation of Th1 cells [17]. The Th1 cells in turn generate large amounts of IFNand strongly potentiate macrophage antimicrobial activity [18], a central mechanism eliminating chronic infectious pathogens [19].…”

VCAM-1/α4β1 Integrin Interaction Is Crucial for Prompt Recruitment of Immune T Cells into the Brain during the Early Stage of Reactivation of Chronic Infection with Toxoplasma gondii To Prevent Toxoplasmic Encephalitis

“…Immunohistochemical study revealed that VCAM-1 and ICAM-1 are the two cerebrovascular endothelial adhesion molecules expressed in both wild-type and SCID mice during the chronic stage of infection. Although the cerebrovascular VCAM-1 expression following the infection is largely dependent on IFN-␥ (33), microglia in SCID and nude mice and NK cells are able to produce this cytokine in response to T. gondii (41,43,44). IFN-␥ production by these non-T cells appears to be sufficient to upregulate VCAM-1 expression on the cerebral vessels in infected SCID and nude mice.…”

Distribution of parasite stages in tissues of Toxoplasma gondii infected SCID mice and human peripheral blood lymphocyte‐transplanted SCID mice

“…In SCID mice IFN-g, IL-12, TNF-a and TGF-b have important protective activities, whereas IL-6 and IL-10 increase the susceptibility of SCID mice to T. gondii (Hunter et al 1993, Gazzinelli et al 1994. It has been reported that in-vivo treatment with anti-ASGM1 reduces NK cell activity and serum levels of IFN-g in T. gondii infected SCID mice, though this does not result in earlier mortality (Hunter et al 1994). Therefore, in our model, it is possible that increased levels of murine IL-6 and IL-10, due to hu-PBL transplantation and decreased amounts of IFN-g, after the anti-ASGM1 depletion of NK cells, may contribute to the increased parasite burden in transplanted animals.…”