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

Souza-Fonseca-Guimarães, Fernando; Parlato, Marianna; Fitting, Catherine; Cavaillon, Jean‐Marc; Adib‐Conquy, Minou

doi:10.4049/jimmunol.1103616

Cited by 60 publications

(65 citation statements)

References 54 publications

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“…Interestingly, the direct TLR4 stimulation of NK cells did not improve mortality in our model. These data are in line with two recent studies showing that NK cell reactivity to TLR4 agonist, was reduced in a murine model of sepsis-induced immunosuppression [18] and in humans suffering from sepsis or sterile systemic inflammation [32]. Finally, NK cell hyporeactivity to MPLA could be related to haemorrhage-induced decrease in intracellular TLR4.…”

Section: Discussionsupporting

confidence: 79%

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Toll-like receptor-4 agonist in post-haemorrhage pneumonia: role of dendritic and natural killer cells

et al. 2013

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Haemorrhage-induced immunosuppression has been linked to nosocomial infections. We assessed the impact of monophosphoryl lipid A, a Toll/interleukin-1 receptor-domain-containing adaptor protein inducing interferon-biased Toll-like receptor-4 agonist currently used as a vaccine adjuvant in humans, on post-haemorrhage susceptibility to infection.We used a mouse model of post-haemorrhage pneumonia induced by methicillin-susceptible Staphylococcus aureus. Monophosphoryl lipid A was administered intravenously after haemorrhage and before pneumonia onset.Haemorrhage altered survival rate, increased lung damage (neutrophil accumulation, oedema and cytokine release) and altered the functions of dendritic and natural killer cells. Here, we show that monophosphoryl lipid A decreased systemic dissemination of S. aureus and dampened inflammatory lung lesions. Monophosphoryl lipid A partially restored the capacity for antigen presentation and the transcriptional activity in dendritic cells. Monophosphoryl lipid A did not restore the interferon-c mRNA but prevented interleukin-10 mRNA overexpression in natural killer cells compared with untreated mice. Ex vivo monophosphoryl lipid A-stimulated dendritic cells or natural killer cells harvested from haemorrhaged animals were adoptively transferred into mice undergoing post-haemorrhage pneumonia. Stimulated dendritic cells (but not stimulated natural killer cells) improved the survival rate compared with mice left untreated. In vivo depletion of natural killer cells decreased survival rate of monophosphoryl lipid A-treated mice.Dendritic and natural killer cells are critically involved in the beneficial effects of monophosphoryl lipid A within post-haemorrhage pneumonia. @ERSpublications Dendritic cells and NK cells are critically involved in the beneficial effects of MPLA within posthaemorrhage pneumonia

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Section: Discussionsupporting

confidence: 79%

“…5a and b). As previously described in NK cells [18], we failed to detect surface expression of TLR4 on NK cells (data not shown), but intracellular TLR4 levels were decreased in the H and HP groups compared with the control (group S, fig. 5c).…”

Section: Mpla-stimulated Dcs Increase Survival In Mice Undergoing Posmentioning

confidence: 60%

Toll-like receptor-4 agonist in post-haemorrhage pneumonia: role of dendritic and natural killer cells

et al. 2013

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“…36,37 We also recently observed that both NK-cell cytotoxicity and IFN-g production were decreased in sepsis, 38 consistent with similar results obtained in mice. 39 Considering the sequence of opposite events that are at work during sepsis, NK cells might have a dual role in sepsis, first contributing to the amplification of the inflammatory response during the early steps of SIRS and then, impaired during CARS and thus participating to its detrimental consequences. 38,40,41 Our data on B7-H6 expression during inflammation provide a novel perspective on the link between microbial infection and NK-cell activation.…”

Section: Discussionmentioning

confidence: 99%

Induction of B7-H6, a ligand for the natural killer cell–activating receptor NKp30, in inflammatory conditions

Matta

Baratin

Chiche

et al. 2013

Blood

120

128

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• B7-H6 transcripts, B7-H6 cell-surface expression, and sB7-H6 can be induced in inflammatory conditions in vitro and in vivo.• B7-H6 is expressed on proinflammatory CD141 CD16 1 monocytes in sepsis conditions and is linked to an increased mortality.B7-H6, a member of the B7 family of immunoreceptors, is as a cell-surface ligand for the NKp30-activating receptor expressed on natural killer cells. B7-H6 is not detected in normal human tissues at steady state but is expressed on tumor cells. However, whether B7-H6 can be expressed in other conditions remains unknown. We analyzed here the pathways that lead to the expression of B7-H6 in nontransformed cells. In vitro, B7-H6 was induced at the surface of CD14 1 CD16 1 proinflammatory monocytes and neutrophils upon stimulation by ligands of Toll-like receptors or proinflammatory cytokines such as interleukin-1b and tumor necrosis factor a. In these conditions, a soluble form of B7-H6 (sB7-H6) was also produced by activated monocytes and neutrophils. In vivo, B7-H6 was expressed on circulating proinflammatory CD14 1 CD16 1 monocytes in a group of patients in sepsis conditions, and was linked to an increased mortality. sB7-H6 was selectively detected in the sera of patients with gram-negative sepsis and was associated with membrane vesicles that co-sedimented with the exosomal fraction. These findings reveal that B7-H6 is not only implicated in tumor immunosurveillance but also participates in the inflammatory response in infectious conditions. This trial was registered at www.clinicaltrials.gov as #NTC00699868. (Blood. 2013;122(3):394-404)

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“…This phenomenon prominently involves the refractoriness of monocytes/macrophages to challenge with LPS or other PAMPs, an observation also known as endotoxin tolerance [34]. Similarly, in murine spleen cells after experimental polymicrobial sepsis and in blood samples from ICU patients (bacterial sepsis or SIRS), IFN-γ production in response to TLR agonists was lost, resembling the tolerance already described for monocytes [13,14]. In concert, NK cell immunosuppression was also observed in blood samples from trauma patients with brain injury, where poor NK cell recruitment into a BCG-induced granuloma model was noticed [35].…”

Section: Natural Mechanisms Restricting Excessive Nk Cell-mediated Inmentioning

confidence: 94%

“…Recently, we have shown that both murine spleen and human blood NK cells express the bacterial sensors TLR2, TLR4 and TLR9 at the protein level and that they are responsive to their agonists in terms of IFN-γ production in the presence of accessory cytokines [13-15]. In contrast to phagocytes, the activation of NK cells by PAMPs often requires complex crosstalk with other immune cells, as already shown with dendritic cells, polymorphonuclear cells, and so on.…”

Section: Systemic Inflammatory Response Syndrome Sepsis and Naturalmentioning

confidence: 99%

Bench-to-bedside review: Natural killer cells in sepsis - guilty or not guilty?

Souza-Fonseca-Guimarães

Cavaillon

Adib‐Conquy

2013

Crit Care

Self Cite

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Bacterial sepsis and septic shock are complex inflammatory disorders associated with a systemic inflammatory response syndrome. In the most severe cases of infection, an overzealous release of pro-inflammatory cytokines and inflammatory mediators by activated leukocytes, epithelial cells and endothelial cells, known as a 'cytokine storm', leads to deleterious effects such as organ dysfunction and even death. By the end of the 20th century, natural killer (NK) cells were for the first time identified as important players during sepsis. The role of this cell type was, however, double-edged, either 'angel' or 'devil' depending upon the bacterial infection model under study. Bacterial sensors (such as Toll-like receptors) have recently been shown to be expressed at the protein level in these cells. In addition, NK cells are important sources of interferon-γ and granulocyte-macrophage colony-stimulating factor, which are pro-inflammatory cytokines necessary to fight infection but can contribute to deleterious inflammation as well. Interestingly, an adaptative response occurs aimed to silence them, similar to the well-known phenomenon of endotoxin reprogramming.

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

Cited by 60 publications

References 54 publications

Toll-like receptor-4 agonist in post-haemorrhage pneumonia: role of dendritic and natural killer cells

Toll-like receptor-4 agonist in post-haemorrhage pneumonia: role of dendritic and natural killer cells

Induction of B7-H6, a ligand for the natural killer cell–activating receptor NKp30, in inflammatory conditions

Bench-to-bedside review: Natural killer cells in sepsis - guilty or not guilty?

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