Type 1 cytokine/chemokine production by mouse NK cells following activation of their TLR/MyD88-mediated pathways

Sawaki, Junko; Tsutsui, Hiroko; Hayashi, Nobuki; Yasuda, Koubun; Akira, Shizuo; Tanizawa, Takakuni; Nakanishi, Kenji

doi:10.1093/intimm/dxl148

Cited by 75 publications

(71 citation statements)

References 47 publications

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“…In spite of conflicting data on TLR expression in NK cells, several groups have shown that TLR7/TLR8 agonists induce NK cell activation, as judged by CD69 expression, IFN-␥ production, and exertion of their cytotoxic effector function. However, it was also observed that this TLR7/TLR8-induced NK cell activation is crucially dependent on contact with cytokines (e.g., IL-12 or type I IFNs) produced by accessory cells in peripheral blood [24,70,70,71,[73][74][75][76]. Therefore, it is not completely clear yet if the NK activation observed after the addition of TLR7/8 agonists is partially caused by or dependent on direct activation of TLR7 and/or TLR8 in NK cells.…”

Section: Cd8mentioning

confidence: 99%

The Use of TLR7 and TLR8 Ligands for the Enhancement of Cancer Immunotherapy

et al. 2008

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After completing this course, the reader should be able to:1. Describe the subtypes of Toll-like receptor 7 and 8 agonists and their effect on the different components of the antitumor immune response.2. Argue why they are used as stand-alone immunotherapeutic agents.3. Evaluate their potential to improve current approaches of active and passive immunotherapy.This article is available for continuing medical education credit at CME.TheOncologist.com. CME CME ABSTRACT

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Section: Cd8mentioning

confidence: 99%

The Use of TLR7 and TLR8 Ligands for the Enhancement of Cancer Immunotherapy

et al. 2008

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“…Third, as IL-12-stimulated murine NK cells secrete IFN-g in response to polyI:C [22], we compared polyI:C-induced IFN-b production by NK cells from WT and IFNAR1 À/À mice. Murine NK-cell purity (isolated by positive selection followed by FACS sorting) was higher than 99% ( Fig.…”

Section: Autocrine Role Of Ifn-b In Ifn-c Secretion By Nk Cellsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…As an example, the TLR3 agonist polyI:C, which mimics double-strand viral RNA [17], acts synergistically with IL-2 and IL-12 to induce IFN-g production by human NK cells [18][19][20]. Murine NK cells also express functional TLR and produce IFN-g in response to TLR3 agonist [21,22].Although human NK cells have a central role in anti-viral immunity and in the control of adaptive immunity [11], whether they produce type I IFN remained unexplored. We report here that polyI:C induces the secretion of IFN-g by NK cells that acts as an autocrine amplification loop to induce IFN-g secretion.…”

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PolyI:C plus IL‐2 or IL‐12 induce IFN‐γ production by human NK cells via autocrine IFN‐β

et al. 2009

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NK lymphocytes and type I IFN (IFN-a/b) are major actors of the innate anti-viral response that also influence adaptive immune responses. We evaluated type I IFN production by human NK cells in response to polyI:C, a potent type I IFN-inducing TLR3 agonist. PolyI:C plus IL-2/IL-12 induced IFN-b (but not IFN-a) mRNA expression and protein production by highly pure human NK cells and by the human NK cell line NK92. Neutralizing anti-IFNAR1 or anti-IFN-b Ab prevented the production of IFN-c induced by polyI:C plus IL-2/IL-12. Similarly, IFN-c production induced by polyI:C plus IL-12 was reduced in NK cells isolated from IFNAR1 À/À compared with WT mice. The ability of polyI:C plus IL-12 to induce IFN-c production was related to an increase of TLR3, Mda5 and IFNAR expression and by an increase of STAT1 and STAT4 phosphorylation. Collectively, these data demonstrate that NK cells, in response to polyI:C plus IL-2/IL-12, produce IFN-b that induce, in an autocrine manner, the production of IFN-c and thereby highlight that NK cells may control the outcome of protective or injurious immune responses through type I IFN secretion.Key words: IFN-g . NK cells . PolyI:C . Type I IFN IntroductionType I IFN is a multi-member cytokine family, in which IFN-a and -b are the main types of interest from an immunological perspective [1,2]. They are involved in anti-viral immunity and in some immune disorders (such as autoimmune diseases). In addition to directly interfering with viral replication, type I IFN have anti-proliferative and immunoregulatory properties. They bridge innate and adaptive immune responses by inducing DC maturation and favoring antigen cross-presentation [3]. They also act directly on CD8 1 T cells to favor the generation of effector and memory T cells [4]. The expression of type I IFN is induced early upon recognition of viruses or viral moieties by some innate receptors of the TLR or RIG-1-like receptor families [5]. IFN-a is mainly secreted by plasmacytoid DC in response to viral nucleic acids recognized by TLR7 and 9 [6]. IFN-b mRNA expression is induced in numerous cell types by TLR stimulation [7,8]. IFN-b has a short half-time, is difficult to quantify, and its secretion is mainly evidenced indirectly by neutralizing its activity in in vitro assay [9]. Owing to the central role of type I IFN in the [11]. These cells kill virally infected cells and tumoral cells in the absence of prior activation [11,12]. NK-cell cytotoxic activity is tightly regulated by inhibitory and activatory receptors [13]. Consequently, NK cells are important during the early phases of viral infection, while antigen-specific T-and B-cell responses are generated. In addition to cytotoxic properties, NK cells have immunoregulatory functions. Through the expression of cell surface molecules and the secretion of cytokines such as IFN-g, they directly modulate macrophages, B and T lymphocyte and DC functions [11,12,14,15]. Consequently, in addition to a protective role in anti-tumor and antiviral immunity, it is now suggested that NK c...

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“…NK cells have been shown to express TLRs, mainly by measuring mRNA. However, their expressions (mRNA or surface expression) remain controversial (11)(12)(13)(14).…”

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confidence: 99%

NK Cell Tolerance to TLR Agonists Mediated by Regulatory T Cells after Polymicrobial Sepsis

Souza-Fonseca-Guimarães

Parlato

Fitting

et al. 2012

The Journal of Immunology

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As sensors of infection, innate immune cells are able to recognize pathogen-associated molecular patterns by receptors such as TLRs. NK cells present in many tissues contribute to inflammatory processes, particularly through the production of IFN-γ. They may display a protective role during infection but also a detrimental role during sterile or infectious systemic inflammatory response syndrome. Nevertheless, the exact status of NK cells during bacterial sepsis and their capacity directly to respond to TLR agonists remain unclear. The expression of TLRs in NK cells has been widely studied by analyzing the mRNA of these receptors. The aim of this study was to gain insight into TLR2/TLR4/TLR9 expression on/in murine NK cells at the protein level and determine if their agonists were able to induce cytokine production. We show, by flow cytometry, a strong intracellular expression of TLR2 and a low of TLR4 in freshly isolated murine spleen NK cells, similar to that of TLR9. In vitro, purified NK cells respond to TLR2, TLR4, and TLR9 agonists, in synergy with activating cytokines (IL-2, IL-15, and/or IL-18), and produce proinflammatory cytokines (IFN-γ and GM-CSF). Finally, we explored the possible tolerance of NK cells to TLR agonists after a polymicrobial sepsis (experimental peritonitis). For the first time, to our knowledge, NK cells are shown to become tolerant in terms of proinflammatory cytokines production after sepsis. We show that this tolerance is associated with a reduction of the CD27+CD11b− subset in the spleen related to the presence of regulatory T cells and mainly mediated by TGF-β.

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Type 1 cytokine/chemokine production by mouse NK cells following activation of their TLR/MyD88-mediated pathways

Cited by 75 publications

References 47 publications

The Use of TLR7 and TLR8 Ligands for the Enhancement of Cancer Immunotherapy

The Use of TLR7 and TLR8 Ligands for the Enhancement of Cancer Immunotherapy

PolyI:C plus IL‐2 or IL‐12 induce IFN‐γ production by human NK cells via autocrine IFN‐β

NK Cell Tolerance to TLR Agonists Mediated by Regulatory T Cells after Polymicrobial Sepsis

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