TAP-1 indirectly regulates CD4+ T cell priming in Toxoplasma gondii infection by controlling NK cell IFN- production (original) (raw)
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Infection and Immunity, 2000
Resistance to Toxoplasma gondii has been shown to be mediated by gamma interferon (IFN-␥) produced by NK, CD4 ؉ , and CD8 ؉ T cells. While studies of SCID mice have implicated NK cells as the source of the cytokine in acute infection, several lines of evidence suggest that IFN-␥ production by CD4 ؉ T lymphocytes also plays an important role in controlling early parasite growth. To evaluate whether this function is due to nonspecific as opposed to T-cell receptor (TCR)-dependent stimulation by the parasite, we have examined the resistance to T. gondii infection of pigeon cytochrome c transgenic (PCC-Tg) Rag-2 ؊/؊ mice in which all CD4 ؉ T lymphocytes are unreactive with the protozoan. When inoculated with the ME49 strain, PCC-Tg animals exhibited only temporary control of acute infection and succumbed by day 17. Intracellular cytokine staining by flow cytometry revealed that, in contrast to infected nontransgenic controls, infected PCC-Tg animals failed to develop IFN-␥-producing CD4 ؉ T cells. Moreover, the CD4 ؉ lymphocytes from these mice showed no evidence of activation as judged by lack of upregulated expression of CD44 or CD69. Nevertheless, when acutely infected transgenic mice were primed by PCC injection, the lymphokine responses measured after in vitro antigen restimulation displayed a strong Th1 bias which was shown to be dependent on endogenous interleukin 12 (IL-12). The above findings argue that, while T. gondii-induced IL-12 cannot trigger IFN-␥ production by CD4 ؉ T cells in the absence of TCR ligation, the pathogen is able to nonspecifically promote Th1 responses against nonparasite antigens, an effect that may explain the immunostimulatory properties of T. gondii infection.
Infection and immunity, 2004
Protective immunity in mice infected with Toxoplasma gondii is mainly mediated by NK cells, CD4 and CD8 T cells, and type 1 cytokines, such as gamma interferon (IFN-gamma). To clarify the roles of NK cells and IFN-gamma in protection against primary congenital toxoplasmosis, we used recombination activating gene 2 knockout (RAG-2(-/-)) mice, which lack T and B lymphocytes, in comparison with the wild-type BALB/c model. RAG-2(-/-) mice had a significantly lower risk of fetal toxoplasmosis than BALB/c mice (25 versus 63.9%; P = 0.003). This protection was associated with an increased number of maternal NK cells, IFN-gamma secretion by spleen cells, and decreased parasitemia. In the RAG-2(-/-) mice, NK cell depletion increased both the rate of fetal infection, to 56.5% (P = 0.02), and the blood parasite burden. Conversely, in the BALB/c mice, this treatment did not modify maternofetal transmission or the blood parasite burden. Neutralization of IFN-gamma in both infected RAG-2(-/-) and...
The Journal of Immunology
Mice lacking the common cytokine receptor γ-chain (γc) gene exhibit defective development of NK cells and CD8+ T cells and greatly diminished production of IFN-γ. Because resistance of SCID mice to Toxoplasma gondii requires IL-12-dependent IFN-γ production by NK cells, we expected that γc-deficient mice would succumb rapidly to the parasite. Surprisingly, however, most γc-deficient mice survived the acute phase of T. gondii infection. As in wild-type mice, this resistance required IL-12 and IFN-γ; nevertheless, whereas wild-type mice depleted of CD4+ T cells survived, anti-CD4+ treated γc-deficient mice displayed diminished production of IFN-γ and all succumbed to acute infection. These data not only reveal a role for CD4+ T lymphocytes in IFN-γ-dependent host defense but also establish SCID and γc-deficient mice as powerful complementary tools for assessing the function of NK vs CD4+ T cells in immunopathophysiologic responses.
Transmission of Toxoplasma gondii from Infected Dendritic Cells to Natural Killer Cells
Infection and Immunity, 2009
The obligate intracellular parasite Toxoplasma gondii can actively infect any nucleated cell type, including cells from the immune system. In the present study, we observed that a large number of natural killer (NK) cells were infected by T. gondii early after intraperitoneal inoculation of parasites into C57BL/6 mice.
Frontiers in Immunology, 2016
Conventional natural killer (cNK) cells, members of group 1 innate lymphoid cells, are a diverse cell subpopulation based on surface receptor expression, maturation, and functional potential. cNK cells are critical for early immunity to Toxoplasma gondii via IFNγ production. Acute cNK cell responses to infection with different strains of T. gondii have not yet been characterized in detail. Here, we comprehensively performed this analysis with Type I virulent RH, Type II avirulent ME49, and fully attenuated Type I cps1-1 strains. In response to these three parasite strains, murine cNK cells produce IFNγ and become cytotoxic and polyfunctional (IFNγ+CD107a+) at the site of infection. In contrast to virulent RH and avirulent ME49 T. gondii strains, attenuated cps1-1 induced only local cNK cell responses. Infections with RH and ME49 parasites significantly decreased cNK cell frequency and numbers in spleen 5 days post infection compared with cps1-1 parasites. cNK cell subsets expressing activating receptors Ly49H, Ly49D, and NKG2D and inhibitory receptors Ly49I and CD94/NKG2A were similar when compared between the strains and at 5 days post infection. cNK cells were not proliferating (Ki67−) 5 days post infection with any of the strains. cNK cell maturation as measured by CD27, CD11b, and KLRG1 was affected after infection with different parasite strains. RH and ME49 infection significantly reduced mature cNK cell frequency and increased immature cNK cell populations compared with cps1-1 infection. Interestingly, KLRG1 was highly expressed on immature cNK cells after RH infection. After RH and ME49 infections, CD69+ cNK cells in spleen were present at higher frequency than after cps1-1 infection, which may correlate with loss of the mature cNK cell population. Cytokine multiplex analysis indicated cNK cell responses correlated with peritoneal exudate cell, spleen, and serum proinflammatory cytokine levels, including IL-12. qPCR analysis of parasite-specific B1 gene revealed that parasite burdens may affect cNK cell responses. This study demonstrates infection with RH and ME49 parasites impacts cNK cell maturation during acute T. gondii infection. Different cNK cell responses could impact early immunity and susceptibility to these strains.
Infection and immunity, 1994
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-gamma). 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-gamma 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-gamma 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-gamma in serum but did not alter time to death. Spleen cells from infected mice produced higher levels of IFN-gamma 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 t...
Infection and Immunity, 2005
CD8 ؉ T-cell immunity plays an important role in protection against intracellular infections. Earlier studies have shown that CD4 ؉ T-cell help was needed for launching in vivo CD8 ؉ T-cell activity against these pathogens and tumors. However, recently CD4 ؉ T-cell-independent CD8 responses during several microbial infections including those with Toxoplasma gondii have been described, although the mechanism is not understood. We now demonstrate that, in the absence of CD4 ؉ T cells, T. gondii-infected mice exhibit an extended NK cell response, which is mediated by continued interleukin-12 (IL-12) secretion. This prolonged NK cell response is critical for priming parasite-specific CD8 ؉ T-cell immunity.
CCR5 Is Essential for NK Cell Trafficking and Host Survival following Toxoplasma gondii Infection
PLOS Pathogens, 2006
The host response to intracellular pathogens requires the coordinated action of both the innate and acquired immune systems. Chemokines play a critical role in the trafficking of immune cells and transitioning an innate immune response into an acquired response. We analyzed the host response of mice deficient in the chemokine receptor CCR5 following infection with the intracellular protozoan parasite Toxoplasma gondii. We found that CCR5 controls recruitment of natural killer (NK) cells into infected tissues. Without this influx of NK cells, tissues from CCR5-deficient (CCR5 À/À ) mice were less able to generate an inflammatory response, had decreased chemokine and interferon c production, and had higher parasite burden. As a result, CCR5 À/À mice were more susceptible to infection with T. gondii but were less susceptible to the immune-mediated tissue injury seen in certain inbred strains. Adoptive transfer of CCR5 þ/þ NK cells into CCR5 À/À mice restored their ability to survive lethal T. gondii infection and demonstrated that CCR5 is required for NK cell homing into infected liver and spleen. This study establishes CCR5 as a critical receptor guiding NK cell trafficking in host defense. Citation: Khan IA, Thomas SY, Moretto MM, Lee FS, Islam SA, et al. (2006) CCR5 is essential for NK cell trafficking and host survival following Toxoplasma gondii infection. PLoS Pathog 2(6): e49.
IFN-γ-induced Cell Autonomous Immunity to Toxoplasma gondii
Journal of Bacteriology & Parasitology, 2012
Toxoplasma gondii is an obligate intracellular parasite that causes the disease toxoplasmosis. This highly successful parasite is able to infect virtually any warm blooded vertebrate host and host cell even though the definitive host is felidae. Here, we focus on IFN-γ-inducible cell autonomous immunity to T. gondii and mechanisms which the parasite has evolved to evade intracellular antimicrobial defenses. These are discussed in the context of co-evolution of T. gondii with its murine intermediate host.
Toxoplasmosis, 1993
Cell-mediated immunity has long been recognized to play a crucial role in resistance to Toxoplasma gondii. Nevertheless, it is only within recent years that the events involved in cellular control of acute and chronic infection have begun to be defined. An important breakthrough occurred when Suzuki and Remington [Suzuki et al 1988] discovered the central role played by IFN-y in resistance to new infection as well as in the control of re-activation. While the key effector function of this cytokine has now been confirmed, its mechanism of action remains poorly understood. When spleen cells from infected mice or mice vaccinated with the ts-4 mutant are stimulated in vitro with toxoplasma antigens or mitogen, most of the IFNy produced is derived from CD4+ T lymphocytes [Gazzinelli et al 1991, 1992]. Nevertheless, depletion studies performed in both animal models reveal that removal of CD4 + cells fails to ablate resistance. Simultaneous depletion of CD8 + cells, which produce much smaller quantities of the cytokine in vitro, is necessary for full ablation. Moreover, in the vaccine model, a highly significant loss of resistance occurs in mice depleted of CD8+ cells alone. However, when mice are treated with anti-CD4+ antibodies during as opposed to after vaccination, they fail to display immunity to challenge [Gazzinelli, et al 1991]. These findings are consistent with the hypothesis (Figure 1) that CD4 + cells are not the major effector cells of resistance to T. gondii in vivo, but instead their major role is to provide helper function (presumably in the form of IL-2) to CD8 + effector cells or to act as a secondary source of IFN-y. The reason why CD4+ lymphocytes, which produce high levels ofIFN-y in vitro, are not sufficient to mediate protection in vivo is not clear, but may relate to the