Interaction between conventional dendritic cells and natural killer cells is integral to the activation of effective antiviral immunity

181

169

At an early phase of viral infection, contact and cooperation between dendritic cells (DCs) and NK cells activates innate immunity, and also influences recruitment, when needed, of adaptive immunity. Influenza, an adaptable fast-evolving virus, annually causes acute, widespread infections that challenge the innate and adaptive immunity of humanity. In this study, we dissect and define the molecular mechanisms by which influenza-infected, human DCs activate resting, autologous NK cells. Three events in NK cell activation showed different requirements for soluble mediators made by infected DCs and for signals arising from contact with infected DCs. IFN-α was mainly responsible for enhanced NK cytolysis and also important for CD69 up-regulation, whereas IL-12 was necessary for enhancing IFN-γ production. Increased CD69 expression and IFN-γ production, but not increased cytolysis, required recognition of influenza-infected DCs by two NK cell receptors: NKG2D and NKp46. Abs specific for these receptors or their known ligands (UL16-binding proteins 1–3 class I-like molecules for NKG2D and influenza hemagglutinin for NKp46) inhibited CD69 expression and IFN-γ production. Activation of NK cells by influenza-infected DCs and polyinosinic:polycytidylic acid (poly(I:C))-treated DCs was distinguished. Poly(I:C)-treated DCs did not express the UL16-binding protein 3 ligand for NKG2D, and in the absence of the influenza hemagglutinin there was no involvement of NKp46.

Section: Discussioncontrasting

confidence: 76%

Section: Nkp46 and Nkg2d Recognition Of Infected Dendritic Cells Is Nmentioning

confidence: 50%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

NKp46 and NKG2D Recognition of Infected Dendritic Cells Is Necessary for NK Cell Activation in the Human Response to Influenza Infection

Draghi

Pashine

Sanjanwala

et al. 2007

181

169

“…Notably, the ligand on MCA-transformed cells undergoes immune editing by NKp46/NCR1 pressure (14), whereas the ligand on D122 cells described in this study apparently does not. Finally, we have recently shown that a ligand for NKp46/NCR1 is expressed by human and mouse b cells (27,28), and it was also demonstrated that upon human CMV infection of dendritic cells, an unknown ligand of NKp46/NCR1 is downregulated to prevent NK cell-mediated lysis of the infected dendritic cells (30)(31)(32)(33).…”

Section: Discussionmentioning

confidence: 99%

Recognition and Prevention of Tumor Metastasis by the NK Receptor NKp46/NCR1

Glasner¹,

Ghadially²,

Gur³

et al. 2012

147

119

NK cells employ a variety of activating receptors to kill virally infected and tumor cells. Prominent among these receptors are the natural cytotoxicity receptors (NCRs) (NKp30, NKp44, and NKp46), of which only NKp46 has a mouse ortholog (NCR1). The tumor ligand(s) of NKp46/NCR1 is still unknown, but it was shown that the human NKp46 and the mouse NCR1 are involved in tumor eradication both in vitro and in vivo. Whether any of the NK activating receptors is involved in the prevention of tumor metastasis is unknown. To address this question, we studied the activity of the NK cell receptor NKp46/NCR1 in two spontaneous metastasis models, the B16F10.9 melanoma (B16) and the Lewis lung carcinoma (D122) in the NCR1 knockout mouse that was generated by our group, in various in vitro and in vivo assays. We demonstrated that all B16 and D122 tumors, including those generated in vivo, express an unknown ligand(s) for NKp46/NCR1. We have characterized the properties of the NKp46/NCR1 ligand(s) and demonstrated that NKp46/NCR1 is directly involved in the killing of B16 and D122 cells. Importantly, we showed in vivo that NKp46/NCR1 plays an important role in controlling B16 and D122 metastasis. Thus, to our knowledge, in this study we provide the first evidence for the direct involvement of a specific NK killer receptor in preventing tumor metastasis.

“…These findings are therefore consistent with the observations of Kamath et al (21) who showed that T cell activation is likely a common response to infection and can be mediated by the triggering of several different TLRs. DCs are known to interact with CD4 ϩ T cells and recent reports have shown the importance of DC-NK cell interactions in modulating immune responses (5,6,22). Interestingly, when conventional DCs were depleted from transgenic mice, only TLR4 and TLR5 agonists failed to induce significant immune cell recruitment to the draining lymph nodes, showing similarities in DC signaling through TLR4 and TLR5.…”

Section: Discussionmentioning

confidence: 98%

Variable Requirement of Dendritic Cells for Recruitment of NK and T Cells to Different TLR Agonists

Uchida

Scumpia²,

Murasko

et al. 2007

TLRs initiate the host immune response to microbial pathogens by activating cells of the innate immune system. Dendritic cells (DCs) can be categorized into two major groups, conventional DCs (including CD8 ؉ and CD8 ؊ DCs) and plasmacytoid DCs. In mice, these subsets of DCs express a variety of TLRs, with conventional DCs responding in vitro to predominantly TLR3, TLR4, TLR5, and TLR9 ligands, and plasmacytoid DCs responding mainly to TLR7 and TLR9 ligands. However, the in vivo requirement of DCs to initiate immune responses to specific TLR agonists is not fully known. Using mice depleted of >90% of CD11c ؉ MHC class II ؉ DCs, we demonstrate that cellular recruitment, including CD4 ؉ T cell and CX5 ؉ DX5 ؉ NK cell recruitment to draining lymph nodes following the footpad administration of TLR4 and TLR5 agonists, is dramatically decreased upon reduction of DC numbers, but type I IFN production can partially substitute for DCs in response to TLR3 and TLR7 agonists. Interestingly, TLR ligands can activate T cells and NK cells in the draining lymph nodes, even with reduced DC numbers. The findings reveal considerable plasticity in the response to TLR agonists, with TLR4 and TLR5 agonists sharing the requirement of DCs for subsequent lymph node recruitment of NK and T cells.