The direct effects of Toll-like receptor ligands on human NK cell cytokine production and cytotoxicity

Lauzon, Nicole M.; Mian, Firoz; Mackenzie, Randy; Ashkar, Ali A.

doi:10.1016/j.cellimm.2006.08.004

Cited by 134 publications

(110 citation statements)

References 32 publications

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“…NK cells alone were directly activated, as shown by CD69 expression and IFN-g production, reflecting expression of TLR2 on human NK cells (35,69,70) but not on resting CD4 T lymphocytes. Furthermore, CD4 T lymphocyte activation by HSV Ag-pulsed NK cells was confirmed by upregulated CD69 expression, strongly suggesting that both cell types were sources for IFN-g. We further showed that TLR2, HLA-DR, and HLA-DQ were expressed and also coexpressed on a small proportion of unstimulated NK cells, as well as both NK subsets (although MHC II expression decreased on culture in the absence of HSVAgs).…”

Section: Discussionmentioning

confidence: 99%

Herpes Simplex Virus Antigens Directly Activate NK Cells via TLR2, Thus Facilitating Their Presentation to CD4 T Lymphocytes

Kim

Osborne

Zeng

et al. 2012

The Journal of Immunology

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NK cells infiltrate human herpetic lesions, but their role has been underexplored. HSV can stimulate innate immune responses via surface TLR2, which is expressed on monocyte-derived dendritic cells (DCs) and NK cells. In this study, UV-inactivated HSV1/2 and immunodominant HSV2 glycoprotein D peptides conjugated to the TLR2 agonist dipalmitoyl-S-glyceryl cysteine stimulated CD4 T lymphocyte IFN-γ responses within PBMCs or in coculture with monocyte-derived DCs. NK cells contributed markedly to the PBMC responses. Furthermore, NK cells alone were activated directly by both Ags, also upregulating HLA-DR and HLA-DQ and then they activated autologous CD4 T lymphocytes. Using Transwells, Ag-stimulated NK cells and CD4 T lymphocytes were shown to interact through both cell-to-cell contact and cytokines, differing in relative importance in different donors. A distinct immunological synapse between Ag-stimulated NK cells and CD4 T lymphocytes was observed, indicating the significance of their cell-to-cell contact. A large proportion (57%) of NK cells was also in contact with CD4 T lymphocytes in the dermal infiltrate of human recurrent herpetic lesions. Thus, NK cells stimulated by TLR2-activating HSV Ags can present Ag alone or augment the role of DCs in vitro and perhaps in herpetic lesions or draining lymph nodes. In addition to DCs, NK cells should be considered as targets for adjuvants during HSV vaccine development.

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Section: Discussionmentioning

confidence: 99%

Herpes Simplex Virus Antigens Directly Activate NK Cells via TLR2, Thus Facilitating Their Presentation to CD4 T Lymphocytes

Kim

Osborne

Zeng

et al. 2012

The Journal of Immunology

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“…Various detection methods have yielded conflicting results (mRNA or surface expression) (7)(8)(9)(10). We recently showed that murine NK cells do indeed express TLR2, TLR4, and TLR9 at the protein level.…”

Section: Natural Killer (Nk)mentioning

confidence: 99%

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

Parlato

Oliveira

et al. 2013

Journal of Biological Chemistry

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Background: NK produce IFN-␥ and GM-CSF in response to CpG-ODN in the presence of accessory cytokines. Results: This production involves NF-B, STAT3, UNC93b1 and IL-12. IFN-␥ is MyD88-and TLR9-dependent, whereas GM-CSF depends on the adaptor STING. Conclusion: NK present an alternative mechanism of sensing of CpG-ODN. Significance:These results open new horizons in the understanding of NK cells activation by microbial DNA.

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“…NK cells were purified from the spleen and lungs of naive or infected mice. Purified NK cells (1.5 3 10 5 ) were cultured in the presence or absence of AMs (4.5 3 10 5 ) (1NK/3AM ratio) with or without 4 mg/ml staphylococcal PGN (Sigma-Aldrich) and 200 U/ml rIL-2 for 24 h at 37˚C, 5% CO 2 as previously described (26). In some cases, prior to coculturing with AMs, purified NK cells were treated with 3 mg/ml recombinant murine TNF-a and then incubated overnight at 37˚C, 5% CO 2 .…”

Section: In Vitro Coculture Of Ams and Nk Cellsmentioning

confidence: 99%

Influenza Infection Leads to Increased Susceptibility to Subsequent Bacterial Superinfection by Impairing NK Cell Responses in the Lung

Small

Shaler

McCormick

et al. 2010

The Journal of Immunology

Self Cite

195

160

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Influenza viral infection is well-known to predispose to subsequent bacterial superinfection in the lung but the mechanisms have remained poorly defined. We have established a murine model of heterologous infections by an H1N1 influenza virus and Staphylococcus aureus. We found that indeed prior influenza infection markedly increased the susceptibility of mice to secondary S. aureus superinfection. Severe sickness and heightened bacterial infection in flu and S. aureus dual-infected animals were associated with severe immunopathology in the lung. We further found that flu-experienced lungs had an impaired NK cell response in the airway to subsequent S. aureus bacterial infection. Thus, adoptive transfer of naive NK cells to the airway of prior flu-infected mice restored flu-impaired antibacterial host defense. We identified that TNF-α production of NK cells played an important role in NK cell-mediated antibacterial host defense as NK cells in flu-experienced lungs had reduced TNF-α expression and adoptive transfer of TNF-α–deficient NK cells to the airway of flu-infected mice failed to restore flu-impaired antibacterial host defense. Defected NK cell function was found to be an upstream mechanism of depressed antibacterial activities by alveolar macrophages as contrast to naive wild-type NK cells, the NK cells from flu-infected or TNF-α–deficient mice failed to enhance S. aureus phagocytosis by alveolar macrophages. Together, our study identifies the weakened NK cell response in the lung to be a novel critical mechanism for flu-mediated susceptibility to bacterial superinfection.

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The direct effects of Toll-like receptor ligands on human NK cell cytokine production and cytotoxicity

Cited by 134 publications

References 32 publications

Herpes Simplex Virus Antigens Directly Activate NK Cells via TLR2, Thus Facilitating Their Presentation to CD4 T Lymphocytes

Herpes Simplex Virus Antigens Directly Activate NK Cells via TLR2, Thus Facilitating Their Presentation to CD4 T Lymphocytes

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)

Influenza Infection Leads to Increased Susceptibility to Subsequent Bacterial Superinfection by Impairing NK Cell Responses in the Lung

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