The Natural Cytotoxicity Receptor 1 Contribution to Early Clearance of Streptococcus pneumoniae and to Natural Killer-Macrophage Cross Talk

The Shraga Segal Department of Microbiology and Immunology and the National Institute for Biotechnology in the Negev, Ben Gurion University of the Negev, Beer Sheva, Israel.
PLoS ONE (Impact Factor: 3.23). 08/2011; 6(8):e23472. DOI: 10.1371/journal.pone.0023472
Source: PubMed


Natural killer (NK) cells serve as a crucial first line of defense against tumors, viral and bacterial infections. We studied the involvement of a principal activating natural killer cell receptor, natural cytotoxicity receptor 1 (NCR1), in the innate immune response to S. pneumoniae infection. Our results demonstrate that the presence of the NCR1 receptor is imperative for the early clearance of S. pneumoniae. We tied the ends in vivo by showing that deficiency in NCR1 resulted in reduced lung NK cell activation and lung IFNγ production at the early stages of S. pneumoniae infection. NCR1 did not mediate direct recognition of S. pneumoniae. Therefore, we studied the involvement of lung macrophages and dendritic cells (DC) as the mediators of NK-expressed NCR1 involvement in response to S. pneumoniae. In vitro, wild type BM-derived macrophages and DC expressed ligands to NCR1 and co-incubation of S. pneumoniae-infected macrophages/DC with NCR1-deficient NK cells resulted in significantly lesser IFNγ levels compared to NCR1-expressing NK cells. In vivo, ablation of lung macrophages and DC was detrimental to the early clearance of S. pneumoniae. NCR1-expressing mice had more potent alveolar macrophages as compared to NCR1-deficient mice. This result correlated with the higher fraction of NCR1-ligand(high) lung macrophages, in NCR1-expressing mice, that had better phagocytic activity compared to NCR1-ligand(dull) macrophages. Overall, our results point to the essential contribution of NK-expressed NCR1 in early response to S. pneumoniae infection and to NCR1-mediated interaction of NK and S. pneumoniae infected-macrophages and -DC.

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    • "In contrast, NKp46-expressing wild type mice appear to be endowed with potent alveolar macrophage responses as compared to NCR1-deficient mice. This result correlates with the higher fraction of NKp46 ligand on lung macrophages in NCR1-expressing mice that are also equipped with better phagocytic activity compared to that of macrophages with lower or negative surface levels of NKp46 ligands (Elhaik-Goldman et al., 2011). "
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    ABSTRACT: Natural cytotoxicity receptors (NCRs) have been classically defined as activating receptors delivering potent signals to Natural Killer (NK) cells in order to lyze harmful cells and to produce inflammatory cytokines. Indeed, the elicitation of NK cell effector functions after engagement of NCRs with their ligands on tumor or virus infected cells without the need for prior antigen recognition is one of the main mechanisms that allow a rapid clearance of target cells. The three known NCRs, NKp46, NKp44, and NKp30, comprise a family of germ-line encoded Ig-like trans-membrane (TM) receptors. Until recently, NCRs were thought to be NK cell specific surface molecules, thus making it possible to easily distinguish NK cells from phenotypically similar cell types. Moreover, it has also been found that the surface expression of NKp46 is conserved on NK cells across mammalian species. This discovery allowed for the use of NKp46 as a reliable marker to identify NK cells in different animal models, a comparison that was not possible before due to the lack of a common and comprehensive receptor repertoire between different species. However, several studies over the recent few years indicated that NCR expression is not exclusively confined to NK cells, but is also present on populations of T as well as of NK-like lymphocytes. These insights raised the hypothesis that the induced expression of NCRs on certain T cell subsets is governed by defined mechanisms involving the engagement of the T cell receptor (TCR) and the action of pro-inflammatory cytokines. In turn, the acquisition of NCRs by T cell subsets is also associated with a functional independence of these Ig-like TM receptors from TCR signaling. Here, we review these novel findings with respect to NCR-mediated functions of NK cells and we also discuss the functional consequences of NCR expression on non-NK cells, with a particular focus on the T cell compartment.
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    • "In addition, other NK activating receptor may also contribute to lysis of NK cells during the interaction with macrophages. NCR1 (murine NKp46) was reported to be important for NK cell activation during the interaction with S. pneumoniae-infected BMMQ [34]. In human, IFN-γ production of NK cell was shown require the interaction of DNAM-1 and 2B4 with their ligands on macrophage exposure to LPS or bacillus Calmette–Guérin [35]. "
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    ABSTRACT: Natural killer (NK) cells and their crosstalk with other immune cells are important for innate immunity against tumor. To explore the role of the interaction between NK cells and macrophages in the regulation of anti-tumor activities of NK cells, we here demonstrate that poly I:C-treated macrophages increased NK cell-mediated cytotoxicity against target tumor cells in NKG2D-dependent manner. In addition, IL-15, IL-18, and IFN-β secreted by poly I:C-treated macrophages are also involved in NKG2D expression and NK cell activation. Interestingly, the increase in expression of NKG2D ligands on macrophages induced a highly NK cell-mediated cytotoxicity against tumor cells, but not against macrophages themselves. Notably, a high expression level of Qa-1, a NKG2A ligand, on macrophages may contribute to such protection of macrophages from NK cell-mediated killing. Furthermore, Qa-1 or NKG2A knockdown and Qa-1 antibody blockade caused the macrophages to be sensitive to NK cytolysis. These results suggested that macrophages may activate NK cells to attack tumor by NKG2D recognition whereas macrophages protect themselves from NK lysis via preferential expression of Qa-1.
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    • "Several groups have shown an upregulation of CD69 at the NK cell surface, the production of IFN-γ and the degranulation of NK cells when monocytes/macrophages were previously stimulated by molecules like Lacto-N-fucopentaose III, poly I:C, CpG DNA, and LPS (Chace et al., 1997; Scott et al., 2004; Atochina and Harn, 2005; Basu et al., 2009; Bellora et al., 2010; Zhou et al., 2012). Infection by parasites, like P. falciparum and Leishmania (Aranha et al., 2005; Baratin et al., 2005), or viruses, like influenza A virus, Sendai virus, human cytomegalovirus (Siren et al., 2004; Romo et al., 2011), or bacteria like Salmonella, M. tuberculosis, E. faecalis, S. aureus, Lactobacillus, S. pneumonia, and B. anthracis, has the same effects (Brill et al., 2001; Haller et al., 2002; Schierloh et al., 2005; Denis et al., 2007; Newman and Riley, 2007; Lapaque et al., 2009; Takayama et al., 2010; Elhaik-Goldman et al., 2011; Klezovich-Benard et al., 2012; Souza-Fonseca-Guimaraes et al., 2012). "
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    ABSTRACT: The interaction between natural killer (NK) cells and different other immune cells like T cells and dendritic cells is well-described, but the crosstalk with monocytes or macrophages and the nature of ligands/receptors implicated are just emerging. The macrophage-NK interaction is a major first-line defense against pathogens (bacteria, viruses, fungi, and parasites). The recruitment and the activation of NK cells to perform cytotoxicity or produce cytokines at the sites of inflammation are important to fight infections. The two main mechanisms by which macrophages can prime NK cells are (1) activation through soluble mediators such as IL-12, IL-18, and (2) stimulation through direct cell-to-cell contact. We will discuss the progress in matters of modulation of NK cell functions by monocytes and macrophages, in the steady state and during diseases.
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