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Activation Receptor-Dependent IFN-? Production by NK Cells Is Controlled by Transcription, Translation, and the Proteasome.

ABSTRACT: NK cells can recognize target cells such as virus-infected and tumor cells through integration of activation and inhibitory receptors. Recognition by NK cells can lead to direct lysis of the target cell and production of the signature cytokine IFN-?. However, it is unclear whether stimulation through activation receptors alone is sufficient for IFN-? production. In this study, we show that NK activation receptor engagement requires additional signals for optimal IFN-? production, which could be provided by IFN-? or IL-12. Stimulation of murine NK cells with soluble Abs directed against NK1.1, Ly49H, Ly49D, or NKp46 required additional stimulation with cytokines, indicating that a range of activation receptors with distinct adaptor molecules require additional stimulation for IFN-? production. The requirement for multiple signals extends to stimulation with primary m157-transgenic target cells, which triggers the activation receptor Ly49H, suggesting that NK cells do require multiple signals for IFN-? production in the context of target cell recognition. Using quantitative PCR and RNA flow cytometry, we found that cytokines, not activating ligands, act on NK cells to express Ifng transcripts. Ly49H engagement is required for IFN-? translational initiation. Results using inhibitors suggest that the proteasome-ubiquitin-IKK-TPL2-MNK1 axis was required during activation receptor engagement. Thus, this study indicates that activation receptor-dependent IFN-? production is regulated on the transcriptional and translational levels.

SUBMITTER: Piersma SJ

PROVIDER: S-EPMC6760998 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Activation Receptor-Dependent IFN-γ Production by NK Cells Is Controlled by Transcription, Translation, and the Proteasome.

Piersma Sytse J SJ Pak-Wittel Melissa A MA Lin Andrea A Plougastel-Douglas Beatrice B Yokoyama Wayne M WM

Journal of immunology (Baltimore, Md. : 1950) 20190823 7

NK cells can recognize target cells such as virus-infected and tumor cells through integration of activation and inhibitory receptors. Recognition by NK cells can lead to direct lysis of the target cell and production of the signature cytokine IFN-γ. However, it is unclear whether stimulation through activation receptors alone is sufficient for IFN-γ production. In this study, we show that NK activation receptor engagement requires additional signals for optimal IFN-γ production, which could be ...[more]

PMID: 31444264

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Project description:Toxoplasma gondii (T. gondii) is a parasite infecting animals and humans. In intermediate hosts, such as humans or rodents, rapidly replicating tachyzoites drive vigorous innate and adaptive immune responses resulting in bradyzoites that survive within tissue cysts. Activation of the innate immune system is critical during the early phase of infection to limit pathogen growth and to instruct parasite-specific adaptive immunity. In rodents, dendritic cells (DCs) sense T. gondii through TLR11/12, leading to IL-12 production, which activates NK cells to produce IFN-γ as an essential mechanism for early parasite control. Further, C3 can bind to T. gondii resulting in limited complement activation. Here, we determined the role of C5a/C5aR1 axis activation for the early innate immune response in a mouse model of peritoneal T. gondii infection. We found that C5ar1 -/- animals suffered from significantly higher weight loss, disease severity, mortality, and parasite burden in the brain than wild type control animals. Severe infection in C5ar1 -/- mice was associated with diminished serum concentrations of IL-12, IL-27, and IFN-γ. Importantly, the serum levels of pro-inflammatory cytokines, including IL-1α, IL-6, and TNF-α, as well as several CXC and CC chemokines, were decreased in comparison to wt animals, whereas anti-inflammatory IL-10 was elevated. The defect in IFN-γ production was associated with diminished Ifng mRNA expression in the spleen and the brain, reduced frequency of IFN-γ+ NK cells in the spleen, and decreased Nos2 expression in the brain of C5ar1 -/- mice. Mechanistically, DCs from the spleen of C5ar1 -/- mice produced significantly less IL-12 in response to soluble tachyzoite antigen (STAg) stimulation in vivo and in vitro. Our findings suggest a model in which the C5a/C5aR1 axis promotes IL-12 induction in splenic DCs that is critical for IFN-γ production from NK cells and subsequent iNOS expression in the brain as a critical mechanism to control acute T. gondii infection.

Dataset Information

Activation Receptor-Dependent IFN-? Production by NK Cells Is Controlled by Transcription, Translation, and the Proteasome.

Publications

Activation Receptor-Dependent IFN-γ Production by NK Cells Is Controlled by Transcription, Translation, and the Proteasome.

Similar Datasets

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