IL-18 Contributes to Host Resistance Against Infection with<i>Cryptococcus neoformans</i>in Mice with Defective IL-12 Synthesis Through Induction of IFN-γ Production by NK Cells

Kawakami, Kazuyoshi; Koguchi, Yoshinobu; Qureshi, Mahboob; Miyazato, Akiko; Yara, Satomi; Kinjo, Yuki; Iwakura, Yoichiro; Takeda, Kiyoshi; Akira, Shizuo; Kurimoto, Masashi; Saitô, Atsushi

doi:10.4049/jimmunol.165.2.941

Cited by 120 publications

(92 citation statements)

References 46 publications

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“…7,11 This pulmonary cryptococcosis model is a long-term model compared with other published murine models. 8,[23][24][25][26][27] To monitor IL-4 production over time in this long-term model, IL-4 reporter mice, termed 4get mice, were infected, and enhanced green fluorescent protein (eGFP) expression, which is known to correlate with IL-4 transcription, was assessed. 20 There were constitutively eGFP ϩ pulmonary leukocytes in naïve mice ( Figures 1A and 2, A and B), as published by others.…”

Section: Pulmonary Th2 Development Occurs After 6 Weeks Of Infection mentioning

confidence: 99%

Eosinophils Contribute to IL-4 Production and Shape the T-Helper Cytokine Profile and Inflammatory Response in Pulmonary Cryptococcosis

Piehler

Stenzel

Grahnert

et al. 2011

The American Journal of Pathology

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Susceptibility to infection with Cryptococcus neoformans is tightly determined by production of IL-4. In this study, we investigated the time course of IL-4 production and its innate cellular source in mice infected intranasally with C. neoformans. We show that pulmonary IL-4 production starts surprisingly late after 6 weeks of infection. Interestingly, in the lungs of infected mice, pulmonary T helper (Th) cells and eosinophils produce significant amounts of IL-4. In eosinophil-deficient ⌬dblGATA mice, IL-33 receptor-expressing Th2s are significantly reduced, albeit not absent, whereas protective Th1 and Th17 responses are enhanced. In addition, recruitment of pulmonary inflammatory cells during infection with C. neoformans is reduced in the absence of eosinophils. These data expand previous findings emphasizing an exclusively destructive effector function by eosinophilic granulocytes. Moreover, in ⌬dblGATA mice, fungal control is slightly enhanced in the lung; however, dissemination of Cryptococcus is not prevented. Therefore, eosinophils play an immunoregulatory role that contributes to Th2-dependent susceptibility in allergic inflammation during bronchopulmonary mycosis. Cryptococcus neoformans is a facultative intracellular pathogen that is acquired by inhalation of spores and/or desiccated yeasts and leads to latent pulmonary infection in immunocompetent humans. 1 The development of cryptococcal meningitis occurs mainly in immunocompromised HIV-1-infected patients, most likely by reactivation of latent pulmonary C. neoformans infection. 2 It is estimated that 504,000 HIV-1-infected patients die every year from cryptococcal meningitis in sub-Saharan Africa, 3 which surprisingly exceeds the annual death rate of tuberculosis-associated HIV cases. Resistance against C. neoformans primarily involves monocytic effector mechanisms. 4 -6 In this context, T helper (Th) cells are central regulatory players with profound effects. Whereas IL-12-dependent Th1 responses are protective, with an additional contribution by IL-23-dependent Th17 responses, 7-9 Th2 cells producing IL-4, IL-13, and IL-5 are detrimental. 10,11 Studies 12-14 that used i.v. inoculation examined the traversal of the blood-brain barrier by C. neoformans and led to the conclusion that transmigration can occur with intracellular and extracellular fungi. In case of bronchopulmonary infection, dissemination seems to rely more on Th2 cytokines. This allergic Th2-driven inflammation represents the immunopathological pathway promoting disease by allowing cryptococci to grow inside the lung and finally enabling dissemination to the brain, ultimately causing fatal meningoencephalitis. 15 This sequela is accompanied by development of IL-4/IL-13-dependent alternatively activated macrophages, suggesting that those cells may be involved in dissemination. Alternatively activated macrophages are found only in susceptible mice 15 and show significantly reduced control of intracellular growth. 5 In addition, IL-13-dependent mucus production by goblet cells, IL-4 -...

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Section: Pulmonary Th2 Development Occurs After 6 Weeks Of Infection mentioning

confidence: 99%

Eosinophils Contribute to IL-4 Production and Shape the T-Helper Cytokine Profile and Inflammatory Response in Pulmonary Cryptococcosis

Piehler

Stenzel

Grahnert

et al. 2011

The American Journal of Pathology

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“…Important insight into the role of NK cells in immunity to malaria was provided on IL-12-related mechanisms in early stages of the disease in the model. 42 Indeed, infection of mice can be ameliorated by administration of IL-12 early in the course of the infection. Untreated mice died 12 days after infection, while IL-12 treated mice survived.…”

Section: Nk Cells and Malariamentioning

confidence: 99%

Interactions Between Natural Killer Cells, Cortisol and Prolactin in Malaria During Pregnancy

Mavoungou¹

2006

Clinical Medicine & Research

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Natural killer cells derived from pluripotent hematopoietic stem cells are important cells of the immune system that have two main functions: a cytolytic activity and a cytokine-producing capacity. These functions are tightly regulated by numerous activating and inhibitory receptors, including newly discovered receptors that selectively trigger the cytolytic activity in a major histocompatibility complex independent manner. Based on their defining function of spontaneous cytotoxicity without prior immunization, natural killer (NK) cells have been thought to play a critical role in immune surveillance and cancer therapy. New insights into NK cell biology have suggested their major roles in the control of infections, particularly in Plasmodium falciparum infection and in fetal implantation. P. falciparum is the main protozoan parasite responsible for malaria causing 200-300 million clinical cases and killing over 3 million people each year. This review provides an update on NK cell function, ontogeny and biology in order to better understand the role of NK cells in pregnancy in regions where malaria is endemic. Understanding mechanisms of NK cell functions may lead to novel therapeutic strategies for the treatment of human disease, in general, and particularly in the fight against malaria.

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“…Our results with p35,IL-4 Ϫ/Ϫ mice underscore the central role IL-12 plays in resistance to L. major. Resistance to several bacterial and viral infections can be IL-12-independent, although IFN-␥-dependent (45)(46)(47)(48)(49)(50)(51). It was conceivable that in the absence of an IL-4-mediated Th2 response, sufficient IFN-␥ might be produced by IL-12-independent mechanisms to promote resistance.…”

Section: Cd45rbmentioning

confidence: 99%

The Role of IL-12 in Maintaining Resistance toLeishmania major

Park

Hondowicz

Köpf

et al. 2002

The Journal of Immunology

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IL-12p40 is required for the maintenance of resistance during Leishmania major infection. In this study, we addressed how IL-12 mediates this function. First, we demonstrated that both subunits of IL-12, p40 and p35, were required for continued resistance to L. major. Second, using IL-12, IL-4 doubly deficient mice, we investigated the possibility that IL-12 inhibits IL-4-induced outgrowth of Th2 cells that might compete with Th1 cells. We found that even in the absence of a Th2 response, IL-12 was still required to maintain resistance. Next, using adoptive transfer of Thy-1 disparate CD4+ T cells from L. major-healed mice, we were able to show that the loss of a protective response in L. major-infected IL-12-deficient mice is linked with the loss of Th1 cells. In contrast, there was an equal recovery of CD4+ Th1 cells from wild-type and IL-12-deficient mice when transferred into mice that were not challenged with L. major. The ability of Th1 cells to survive regardless of IL-12 levels in the absence of Ag stimulation was confirmed by adoptive transfer studies of CD4+ Th1 cells from DO11.10 TCR transgenic mice. Taken together, these results indicate that, rather than modulating Th2 responses or optimizing IFN-γ production, the critical role for IL-12 in maintaining cell-mediated immunity may be to prevent the loss of Th1 cells during a challenge infection.

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IL-18 Contributes to Host Resistance Against Infection withCryptococcus neoformansin Mice with Defective IL-12 Synthesis Through Induction of IFN-γ Production by NK Cells

Cited by 120 publications

References 46 publications

Eosinophils Contribute to IL-4 Production and Shape the T-Helper Cytokine Profile and Inflammatory Response in Pulmonary Cryptococcosis

Eosinophils Contribute to IL-4 Production and Shape the T-Helper Cytokine Profile and Inflammatory Response in Pulmonary Cryptococcosis

Interactions Between Natural Killer Cells, Cortisol and Prolactin in Malaria During Pregnancy

The Role of IL-12 in Maintaining Resistance toLeishmania major

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