Interferon-γ and Granulocyte/Monocyte Colony-stimulating Factor Production by Natural Killer Cells Involves Different Signaling Pathways and the Adaptor Stimulator of Interferon Genes (STING)

Souza-Fonseca-Guimarães, Fernando; Parlato, Marianna; Oliveira, Rosane B. de; Golenbock, Douglas T.; Fitzgerald, Katherine A.; Shalova, Irina N.; Biswas, Subhra K.; Cavaillon, Jean‐Marc; Adib‐Conquy, Minou

doi:10.1074/jbc.m112.435602

Cited by 26 publications

(21 citation statements)

References 38 publications

(15 reference statements)

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“…We verified the intracellular localization of TLR9 in murine NK cells and found an overlap with the Golgi apparatus in naive cells, as already described in other situations for other cell types 45 . In addition, IL‐15 and IL‐18 alone or together with CpG‐DNA induced the phosphorylation of c‐Jun and that of IκBα, 46 consistent with the literature in which IL‐15 has been shown to activate the JNK and NF‐κB pathways in myeloid cells 47 . However, CpG‐DNA or IL‐15/IL‐18 alone did not induce any IFN‐γ or GM‐CSF secretion.…”

Section: Sensing Of Bacterial Pamps By Tlrs: Cytokine Production and supporting

confidence: 86%

“…In the case of IFN‐γ, we demonstrated an absence of production in myd88 and tlr9 −/− NK cells, which was consistent with the literature. In contrast, GM‐CSF was TLR9‐independent but dependent on STING (stimulator of interferon genes), 46 a cytosolic adaptor recently described for DNA sensing, which localizes near the endoplasmic reticulum in the presence of intracellular DNA 48 . The TLR9‐independent and STING‐dependent cytokine production was specific for NK cells and was not found in macrophages.…”

Section: Sensing Of Bacterial Pamps By Tlrs: Cytokine Production and mentioning

confidence: 94%

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TLR‐mediated activation of NK cells and their role in bacterial/viral immune responses in mammals

et al. 2013

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Natural killer (NK) cells are important in innate immunity, first described as guardians for the detection and clearance of transformed or virus-infected cells. Later, this cell type was revealed to be also able to recognize and respond to bacteria-infected cells. NK cells possess receptors allowing them to sense and respond to viral and bacterial patterns, including Toll-like receptors (TLRs). Initially described in other innate immune cells, particularly monocytes/macrophages, TLRs have more recently been characterized in NK cells. Controversies remain regarding the TLR expression in NK cells and their responsiveness to agonists, specifically the requirement for the presence of accessory cells, such as dendritic cells, or of accessory cytokines (IL-2, IL-12, IL-15 and IL-18) to respond to TLR agonists. Upon TLR activation, NK cells are an important source of IFN-γ and granulocyte macrophage colony-stimulating factor, cytokines necessary to fight infection but that can also contribute to deleterious inflammation if produced in excessive amounts. Here, we review the current knowledge concerning the expression of TLRs in and on NK cells and the responsiveness to their agonists and review the literature on the role of NK cells in the sensing of bacterial or viral patterns and in combatting infection.

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Section: Sensing Of Bacterial Pamps By Tlrs: Cytokine Production and supporting

confidence: 86%

Section: Sensing Of Bacterial Pamps By Tlrs: Cytokine Production and mentioning

confidence: 94%

TLR‐mediated activation of NK cells and their role in bacterial/viral immune responses in mammals

et al. 2013

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“…We show here that targeting DC activation pathways through the TLR ligand amph-CpG, along with use of the CD40 agonist FGK4.5, similarly control Mtb growth. Treatment of DCs with granulocyte–macrophage-colony-stimulating factor (GM-CSF), a by-product of TLR9 stimulation through CpG64 has previously been shown to upregulate CD103 expression65. Thus, it is possible that CpG stimulates CD103 + expression on DCs indirectly through inducing GM-CSF by other lung-resident cells.…”

Section: Discussionmentioning

confidence: 99%

Targeting dendritic cells to accelerate T-cell activation overcomes a bottleneck in tuberculosis vaccine efficacy

et al. 2016

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The development of a tuberculosis (TB) vaccine that induces sterilizing immunity to Mycobacterium tuberculosis infection has been elusive. Absence of sterilizing immunity induced by TB vaccines may be due to delayed activation of mucosal dendritic cells (DCs), and subsequent delay in antigen presentation and activation of vaccine-induced CD4+ T-cell responses. Here we show that pulmonary delivery of activated M. tuberculosis antigen-primed DCs into vaccinated mice, at the time of M. tuberculosis exposure, can overcome the delay in accumulation of vaccine-induced CD4+ T-cell responses. In addition, activating endogenous host CD103+ DCs and the CD40–CD40L pathway can similarly induce rapid accumulation of vaccine-induced lung CD4+ T-cell responses and limit early M. tuberculosis growth. Thus, our study provides proof of concept that targeting mucosal DCs can accelerate vaccine-induced T-cell responses on M. tuberculosis infection, and provide insights to overcome bottlenecks in TB vaccine efficacy.

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“…These cells are well known for their cytolytic activity, 43 have been shown to express intracellular TLR-9 and are activated by CpG. 44,45 Additionally, activated interferon-c-producing NK cells have previously been identified in afferent lymph. 46 The presence of Th17 ILC in afferent lymph remains to be elucidated; however, Th17-related signatures have been observed in afferent lymph 48-72 hr following injection of poly(I:C).…”

Section: Discussionmentioning

confidence: 99%

Transcriptional profile in afferent lymph cells following vaccination with liposomes incorporating CpG

Neeland

Elhay²,

Powell

et al. 2015

Immunology

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SummaryVaccine formulations incorporating innate immune stimulants are highly immunogenic; however, the biological signals that originate in the peripheral tissues at the site of injection and are transmitted to the local lymph node to induce immunity remain unclear. By directly cannulating the ovine afferent lymphatic vessels, we have previously shown that it takes 72 hr for mature antigen-loaded dendritic cells and monocytes to appear within afferent lymph following injection of a liposomal formulation containing the Toll-like receptor ligand CpG. In this present study, we characterize the global transcriptional signatures at this time-point in ovine afferent lymph cells as they migrate from the injection site into the lymphatics following vaccination with a liposome antigen formulation incorporating CpG. We show that at 72 hr post vaccination, liposomes alone induce no changes in gene expression and inflammatory profiles within afferent lymph; however, the incorporation of CpG drives interferon, antiviral and cytotoxic gene programmes. This study also measures the expression of key genes within individual cell types in afferent lymph. Antiviral gene signatures are most prominent in lymphocytes, which may play a significant and unexpected role in sustaining the immune response to vaccination at the site of injection. These findings provide a comprehensive analysis of the in vivo immunological pathways that connect the injection site with the local draining lymph node following vaccination.

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Interferon-γ and Granulocyte/Monocyte Colony-stimulating Factor Production by Natural Killer Cells Involves Different Signaling Pathways and the Adaptor Stimulator of Interferon Genes (STING)

Cited by 26 publications

References 38 publications

TLR‐mediated activation of NK cells and their role in bacterial/viral immune responses in mammals

TLR‐mediated activation of NK cells and their role in bacterial/viral immune responses in mammals

Targeting dendritic cells to accelerate T-cell activation overcomes a bottleneck in tuberculosis vaccine efficacy

Transcriptional profile in afferent lymph cells following vaccination with liposomes incorporating CpG

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