gamma Interferon gene expression and release in human lymphocytes directly activated by Cryptococcus neoformans and Candida albicans

Abstract

Previous studies in our laboratory and others have demonstrated that T and/or NK cells can directly bind to and inhibit the growth of the medically important fungal pathogens Cryptococcus neoformans and Candida albicans by apparently non-major histocompatibility complex-restricted mechanisms. Here, we examined whether this direct interaction between lymphocytes and fungi also results in cytokine gene expression and release. Nonadherent lymphocytes (NAL), isolated from human peripheral blood mononuclear cells by depletion of cells adherent to plastic and nylon wool, released gamma interferon (IFN-␥), but not interleukin-4 (IL-4) and IL-10, following stimulation with C. neoformans yeast cells and C. albicans yeast cells, hyphae, and supernatants. The fungal stimuli also induced IFN-␥ mRNA, with peak gene expression seen at or after 18 h. IFN-␥ release was still seen even when either NK cells or T lymphocytes were depleted by negative selection, suggesting that both cell types can be stimulated by fungi to produce IFN-␥. Release of IFN-␥ from fungusstimulated NAL occurred in the absence of an intact complement system and was not especially enhanced by culture with IL-2 or IL-12. These data expand the mechanisms by which the direct interaction of NAL with fungal targets can lead to immune activation. Moreover, to our knowledge, this is the first demonstration of direct stimulation of T-cell cytokine release by microbial pathogens.

Effect of Interleukin‐10 on the Paracoccidioides brasiliensis Killing by Gamma‐Interferon Activated Human Neutrophils

“…Studies have demonstrated that, in the early phases of L. monocytogenes infection in mice, IFN-γ is produced by these cells (20). Furthermore, IFN-γ gene expression and release by human T lymphocytes and NK cells have been shown to be directly activated by C. neoformans and C. albicans (35). However, other studies have shown that killed yeasts and hyphae of C. albicans inhibit rather than stimulate gamma interferon production by highly purified murine NK cells (46).…”

Direct interactions of human natural killer cells with Cryptococcus neoformans inhibit granulocyte-macrophage colony-stimulating factor and tumor necrosis factor alpha production

“…Our data show that the interaction of the pathogenic fungal target C. neoformans with freshly isolated human NK cells from most individuals results in the inhibition of two constitutively produced cytokines, GM-CSF and TNF-␣. Modulation of NK cell cytokine production as a result of interactions with fungal target cells has been reported previously; however, in each case, cytokine production was augmented rather than reduced (3,8,23). For instance, Candida albicans, a fungal target, which binds to but is not killed by NK cells, stimulates human NK cells to produce increased amounts of GM-CSF and TNF␣ (3,8).…”

“…Previous studies from our laboratory and others have shown that NK cells as well as T lymphocytes can bind to the pathogenic fungus Cryptococcus neoformans and kill the organism (11-16, 21, 22, 28, 29). More recently, Levitz and North have shown that human nonadherent lymphocytes from approximately 60% of the samples that they assessed produced IFN-␥ upon incubation for 18 h with C. neoformans (23). When the nonadherent lymphocytes were depleted of NK cells or T cells prior to stimulation with C. neoformans, the level of IFN-␥ production was reduced, suggesting that both NK and T cells have the potential to make IFN-␥ when stimulated with C. neoformans (23).…”

“…More recently, Levitz and North have shown that human nonadherent lymphocytes from approximately 60% of the samples that they assessed produced IFN-␥ upon incubation for 18 h with C. neoformans (23). When the nonadherent lymphocytes were depleted of NK cells or T cells prior to stimulation with C. neoformans, the level of IFN-␥ production was reduced, suggesting that both NK and T cells have the potential to make IFN-␥ when stimulated with C. neoformans (23). Using purified populations of human NK or T cells, we have found that NK cells from some individuals produce IFN-␥ constitutively, whereas NK cells from other indi-viduals do not.…”

Contemplating the murine test tube: lessons from natural killer cells andCryptococcus neoformans

“…Although C. neoformans does not stimulate the production of IL-10 from human nonadherent peripheral blood mononuclear cells (Levitz & North, 1996), the effect that IL-10 has on NK cell anticryptococcal activity has yet to be determined. The nonadherent peripheral blood mononuclear cells contain a mixed population of both T and NK cells.…”