Bystander Activation of CD8+ T Cells Contributes to the Rapid Production of IFN-γ in Response to Bacterial Pathogens

Abstract

The bacterium Burkholderia pseudomallei causes a life-threatening disease called melioidosis. In vivo experiments in mice have identified that a rapid IFN-γ response is essential for host survival. To identify the cellular sources of IFN-γ, spleen cells from uninfected mice were stimulated with B. pseudomallei in vitro and assayed by ELISA and flow cytometry. Costaining for intracellular IFN-γ vs cell surface markers demonstrated that NK cells and, more surprisingly, CD8+ T cells were the dominant sources of IFN-γ. IFN-γ+ NK cells were detectable after 5 h and IFN-γ+ CD8+ T cells within 15 h after addition of bacteria. IFN-γ production by both cell populations was inhibited by coincubation with neutralizing mAb to IL-12 or IL-18, while a mAb to TNF had much less effect. Three-color flow cytometry showed that IFN-γ-producing CD8+ T cells were of the CD44high phenotype. The preferential activation of NK cells and CD8+ T cells, rather than CD4+ T cells, was also observed in response to Listeria monocytogenes or a combination of IL-12 and IL-18 both in vitro and in vivo. This rapid mechanism of CD8+ T cell activation may be an important component of innate immunity to intracellular pathogens.

Innate Immune Response to Malaria: Rapid Induction of IFN-γ from Human NK Cells by LivePlasmodium falciparum-Infected Erythrocytes

“…We were not surprised to find that the NK cell response was highly IL-12 dependent; this is widely reported for NK cells (39), and has been shown for NK responses to a number of pathogens (40,41). We considered the possibility that differences between donors, and between Ag preparations, in the magnitude of the IFN-␥ response might be due to differences in IL-12 induction.…”

Poor correlation between BCG vaccination-induced T cell responses and protection against tuberculosis

“…It is therefore possible that IFN-␥ secretion was, at least in part, induced by TCRindependent mechanisms. Inflammatory cytokines such as IL-12 and IL-18 can induce TCR-independent IFN-␥ production in conventional effector and memory T cells as well as in natural killer T cells (31)(32)(33). Because inflammatory cytokines should be abundant in heavily infected tissues, such a scenario is likely, and it would be interesting to determine the extent to which TCRindependent IFN-␥ production by T cells contributes to protective immunity against tuberculosis.…”

Binding ofEscherichia coliadhesin AfaE to CD55 triggers cell-surface expression of the MHC class I-related molecule MICA

“…Our data support the concept that MICA, with an expression highly restricted to intestinal epithelium in normal conditions, may signal the presence of bacterial infection to CD8ϩ T or NK cells expressing NKG2D receptors at an early stage of bacterial adhesion. This could be responsible for the rapid antigen-independent activation of CD8ϩ and NK T cells observed in response to bacterial pathogens (40). Although the mechanisms of MICA expression through bacterial adherence are quite different from those recently described by Groh et al (11) in cytomegalovirus-infected cells and by Das et al (12) during M. tuberculosis infection, the role of MICA-NKG2D interaction as a danger signal able to enhance immune responses against pathogens is fully consistent with our data.…”