Functional interactions between dendritic cells and NK cells during viral infection

Self Cite

NK cells vigorously proliferate during viral infections. During the course of murine CMV infection, this response becomes dominated by the preferential proliferation of NK cells that express the activation receptor Ly49H. The factors driving such selective NK cell proliferation have not been characterized. In this study, we demonstrate that preferential NK cell proliferation is dependent on DAP12-mediated signaling following the binding of Ly49H to its virally encoded ligand, m157. Ly49H signaling through DAP12 appears to directly augment NK cell sensitivity to low concentrations of proproliferative cytokines such as IL-15. The impact of Ly49H-mediated signaling on NK cell proliferation is masked in the presence of high concentrations of proproliferative cytokines that nonselectively drive all NK cells to proliferate.

Section: Ly49h Signaling Through Dap12 Does Not Alter Nk Cell Responscontrasting

confidence: 99%

Section: Dap12 Signaling Directly Augments Proproliferative Cytokine mentioning

confidence: 86%

DAP12 Signaling Directly Augments Proproliferative Cytokine Stimulation of NK Cells during Viral Infections

French

Sjölin

Kim

et al. 2006

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“…These studies identified the fact that NK cells responding to MCMV acquired KLRG1, and these cells contained less intracellular IFN-␥ compared with the KLRG1 Ϫ population (12,25). This finding was extended by our recent report on NK subsets where Mac-1 ϩ CD27 Ϫ KLRG1 ϩ cells were found to produce poor levels of IFN-␥ following stimulation with IL-12 and IL-18, cytokines required for the NK cell expansion during MCMV infection (28) or when cocultured with dendritic cells (23). In addition, KLRG1 ϩ NK cells appear to preferentially down-regulate bcl-2 during the course of MCMV infection (25).…”

Section: Discussionmentioning

confidence: 67%

“…The phenotypic maturation of NK cells during MCMV-mediated NK cell division could be a result of exposure of enhanced levels of IL-18 and IL-12 because these cytokines activate NK cells, induce KLRG1 expression, and are known to be important for NK cell response to MCMV (28). Our study monitoring NK cell expansion during development and following transfer to lymphopenic hosts, without an overt inflammatory stimulus to induce these cytokines, provides strong evidence for NK cell maturation being induced by cell division.…”

Section: Discussionmentioning

confidence: 99%

NK Cell Maturation and Peripheral Homeostasis Is Associated with KLRG1 Up-Regulation

Huntington

Tabarias

Fairfax

et al. 2007

Self Cite

293

312

NK cells are important for the clearance of tumors, parasites, and virus-infected cells. Thus, factors that control NK cell numbers and function are critical for the innate immune response. A subset of NK cells express the inhibitory killer cell lectin-like receptor G1 (KLRG1). In this study, we identify that KLRG1 expression is acquired during periods of NK cell division such as development and homeostatic proliferation. KLRG1+ NK cells are mature in phenotype, and we show for the first time that these cells have a slower in vivo turnover rate, reduced proliferative response to IL-15, and poorer homeostatic expansion potential compared with mature NK cells lacking KLRG1. Transfer into lymphopenic recipients indicate that KLRG1− NK cells are precursors of KLRG1+ NK cells and KLRG1 expression accumulates following cell division. Furthermore, KLRG1+ NK cells represent a significantly greater proportion of NK cells in mice with enhanced NK cell numbers such as Cd45−/− mice. These data indicate that NK cells acquire KLRG1 on their surface during development, and this expression correlates with functional distinctions from other peripheral NK cells in vivo.

“…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: 97%

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

Glasner¹,

Ghadially²,

Gur³

et al. 2012

141

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.