Killed Candida albicans Yeasts and Hyphae Inhibit Gamma Interferon Release by Murine Natural Killer Cells

Abstract

Killed yeasts and hyphae of Candida albicans inhibit gamma interferon secretion by highly purified murine NK cells in response to the Toll-like receptor ligands lipopolysaccharide and zymosan. This effect, which is also observed in the presence of NK-activating cytokines (interleukin-2 [IL-2], IL-12, and IL-15), may represent a novel mechanism of immune evasion that contributes to the virulence of C. albicans.Natural killer (NK) cells constitute an important component of innate immunity, being able to limit viremia and tumor burden before the adaptive immune system can be activated. In addition, there is increasing evidence indicating that NK cells may also play a major role in the early defense against bacterial and fungal infections (2, 26). NK cells are able to inhibit the growth of Cryptococcus neoformans (14,17), and the secretion of cytokines (granulocyte-macrophage colony-stimulating factor, tumor necrosis factor alpha, and gamma interferon [IFN-␥]) by activated NK cells up-regulates the fungicidal activity of phagocytic cells, resulting in the growth inhibition of these agents (2, 10, 18). In addition, the interaction of lymphokine-activated killer cells and Candida albicans does not inhibit or kill the fungal pathogen by means of the lymphokine-activated killer cell lytic machinery, but through the secretion of cytokines which have stimulatory effects on phagocytic cells (2). Therefore, antifungal immunity mediated by NK cells appears to occur by the secretion of cytokines that activate phagocytic cells (1, 2). However, whether NK cells are stimulated directly by the fungus or in response to signals generated by activated bystander cells remains to be established (26).The main pattern recognition receptors on the surfaces of phagocytic cells are the Toll-like receptors (TLRs), a family of evolutionarily conserved transmembrane proteins that function as sensors of infection and induce the activation of innate and adaptive immune responses (23, 24). There is evidence indicating that signal transduction mediated by TLRs is essential for murine resistance to disseminated C. albicans infection, basically through the induction of cytokine and chemokine release (4,11,16,(19)(20)(21)(28)(29)(30).During recent years, the expression of TLRs in NK cells has been reported, and several data indicate that NK cells directly recognize and respond to pathogen components through TLRs (3,5,13,15,22). Moreover, TLR-induced stimulation of both dendritic cells and NK cells may play a critical role in inducing NK cells to select the best-fit immature dendritic cells and to facilitate their maturation, thus exerting a regulatory control on the early steps of innate immune responses against pathogens (7, 9, 22). Since the role of NK cells in resistance against many pathogens, including C. albicans, may be mediated by cytokine production, including IFN-␥ production (2, 10, 18, 26), the aim of this work was to study the role of TLRs in triggering IFN-␥ secretion by NK cells in response to yeasts and hyphae of C. albicans. Unexpec...

Pharmacological modulation of GITRL/GITR system: therapeutic perspectives

“…Authors suggest that the survival of GITR −/− mice resulted from lack of mGITRL reverse signalling in DC, causing an increased production of IL‐12 and a prevalent Th1 polarization that favours C. albicans clearance. An additional explanation is that GITR −/− mice have an increased NK function, relevant in control of C. albicans infection (Murciano et al ., 2006).…”

Role of IFN-gamma in immune responses to Candida albicans infections

“…Killed yeasts and hyphae of C. albicans inhibited IFN-γ secretion by highly purified murine NK cells in response to TLR4 and TLR2 ligands, LPS and zymosan, respectively, and this effect was also observed in the presence of NK activating cytokines (IL-2, IL-12 and IL-15) (57). Since the role of NK cells in resistance to C. albicans appears to be basically mediated by cytokine production (including IFN-γ) that activates phagocytic cells (34, 53), its inhibition by C. albicans may favor the survival of the pathogen.…”

Natural Killer Cells and Antifungal Host Response

“…negative effect on the immunoregulatory function of NK cells (17,18,63,64). For example, C. neoformans downregulates the production of GM-CSF and TNF-␣ of unstimulated human NK cells, as assessed by gene expression and supernatant protein levels (64).…”

“…For example, C. neoformans downregulates the production of GM-CSF and TNF-␣ of unstimulated human NK cells, as assessed by gene expression and supernatant protein levels (64). Similarly, A. fumigatus hyphae and C. albicans germ tubes downregulate the levels of IFN-␥, measured in the supernatant of IL-2-prestimulated NK cells (17,63). Additionally, R. oryzae decreases the production of RANTES, which plays an important role in adaptive immunity (18).…”