Interactions between Human NK Cells and Macrophages in Response to Salmonella Infection (original) (raw)
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PLoS ONE, 2014
Natural killer (NK) cells are a critical part of the innate immune defense against viral infections and for the control of tumors. Much less is known about how NK cells contribute to anti-bacterial immunity. NK cell-produced interferon gamma (IFN-c) contributes to the control of early exponential replication of bacterial pathogens, however the regulation of these events remains poorly resolved. Using a mouse model of invasive Salmonellosis, here we report that the activation of the intracellular danger sensor NLRC4 by Salmonella-derived flagellin within CD11c + cells regulates early IFN-c secretion by NK cells through the provision of interleukin 18 (IL-18), independently of Toll-like receptor (TLR)-signaling. Although IL18signalling deficient NK cells improved host protection during S. Typhimurium infection, this increased resistance was inferior to that provided by wild-type NK cells. These findings suggest that although NLRC4 inflammasome-driven secretion of IL18 serves as a potent activator of NK cell mediated IFN-c secretion, IL18-independent NK cell-mediated mechanisms of IFN-c secretion contribute to in vivo control of Salmonella replication.
Regulatory role of peritoneal NK1. 1+ αβ T cells in IL-12 production during Salmonella infection
NK1.1 ؉ ␣ T cells emerge in the peritoneal cavity after an i.p. infection with Salmonella choleraesuis in mice. To elucidate the role of the NK1.1 ؉ ␣ T cells during murine salmonellosis, mice lacking NK1.1 ؉ ␣ T cells by disruption of TCR (TCR ؊/؊),  2 m ( 2 m ؊/؊), or J␣281 (J␣281 ؊/؊) gene were i.p. inoculated with S. choleraesuis. The peritoneal exudate T cells in wild type (wt) mice on day 3 after infection produced IL-4 upon TCR␣ stimulation, whereas those in TCR ؊/؊ ,  2 m ؊/؊ , or J␣281 ؊/؊ mice showed no IL-4 production upon the stimulation, indicating that NK1.1 ؉ ␣ T cells are the main source of IL-4 production at the early phase of Salmonella infection. Neutralization of endogenous IL-4 by administration of anti-IL-4 mAb to wt mice reduced the number of Salmonella accompanied by increased IL-12 production by macrophages after Salmonella infection. The IL-12 production by the peritoneal macrophages was significantly augmented in mice lacking NK1.1 ؉ ␣ T cells after Salmonella infection accompanied by increased serum IFN-␥ level. The aberrantly increased IL-12 production in infected TCR ؊/؊ or J␣281 ؊/؊ mice was suppressed by adoptive transfer of T cells containing NK1.1 ؉ ␣ T cells but not by the transfer of T cells depleted of NK1.1 ؉ ␣ T cells or T cells from J␣281 ؊/؊ mice. Taken together, it is suggested that NK1.1 ؉ ␣ T cells eliciting IL-4 have a regulatory function in the IL-12 production by macrophages at the early phase of Salmonella infection.
Consequences of the crosstalk between monocytes/macrophages and natural killer cells
Frontiers in Immunology, 2013
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.
The Journal of Immunology, 2002
We used human tuberculosis as a model to investigate the role of NK cytotoxic mechanisms in the immune response to intracellular infection. Freshly isolated NK cells and NK cell lines from healthy donors lysed Mycobacterium tuberculosis-infected monocytes to a greater extent than uninfected monocytes. Lysis of infected monocytes was associated with increased expression of mRNA for the NKp46 receptor, but not the NKp44 receptor. Antisera to NKp46 markedly inhibited lysis of infected monocytes. NK cellmediated lysis was not due to reduced expression of MHC class I molecules on the surface of infected monocytes or to enhanced production of IL-18 or IFN-␥. NK cell lytic activity against M. tuberculosis-infected monocytes and NKp46 mRNA expression were reduced in tuberculosis patients with ineffective immunity to M. tuberculosis compared with findings in healthy donors. These observations suggest that 1) the NKp46 receptor participates in NK cell-mediated lysis of cells infected with an intracellular pathogen, and 2) the reduced functional capacity of NK cells is associated with severe manifestations of infectious disease.
Infection and Immunity, 1991
Incubation of large granular lymphocytes (LGL) with glutaraldehyde-fixed bacteria stimulated in the supernatant the production of interferon (IFN), which proved to be mainly IFN-y. Even though IFN-y was produced upon exposure of LGL to bacteria, anti-IFN--y antibodies failed to interfere with induction of cytotoxicity by bacterial contact. Anti-IFN--y receptor antibodies had no effect on the induction of activated killing by bacterial contact either. We also tested the effect of anti-IFN-a antibody, but it failed to interfere with induction of cytotoxicity by bacterial contact. No interleukin-2 (IL-2) was detected in the culture supernatant of bacterially activated LGL by the mouse HT2 cell assay, nor did we detect any IL-2 mRNA in bacterially activated LGL by Northern RNA blot assay. Neutralizing anti-IL-2 antiserum had no effect on the induction of activated killing by bacterial contact, and recombinant IL-4 did not interfere with the induction of activated killing. We then studied the membrane structures involved in bacterially activated killing. Anti-CD18 monoclonal antibody did not interfere with the induction phase of bacterially activated killing. However, both anti-CD18 and anti-CD2 antibodies inhibited the effector phase of bacterially activated killing. The effector pathways utilized by activated LGL depended on the mode of activation in that even though bacterially activated LGL were sometimes blocked by anti-CD2 monoclonal antibody, recombinant-IL-2-stimulated LGL were not. In conclusion, our present results suggest that there may be mediators other than exogenously secreted IFNs and IL-2 which are responsible for the induction of activated killing after bacterial contact. CD18 and CD2 structures were shown to be involved in the effector phase of bacterially activated killing.
Bacterial DNA-Induced NK Cell IFN-γ Production Is Dependent on Macrophage Secretion of IL-12
Clinical Immunology and Immunopathology, 1997
IL-12 production is induced by a number of proin-Bacterial DNA (bDNA) activates B cells and macroflammatory agents (including LPS and IFN-g) and can phages and can augment inflammatory responses by be strongly inhibited by IL-10 (14, 15). Thus, the relainducing release of proinflammatory cytokines. We tive contributions of IL-12 and IL-10 may determine found that bDNA stimulation of mouse spleen cells inwhether an IFN-g-based inflammatory response is sufduced NK cell IFN-g production that was dependent ficient to combat an infection or is excessive to the exupon the presence of unmethylated CpG motifs, and tent that the host is harmed. oligonucleotides with internal CpG motifs could also Microorganisms elicit inflammatory responses by the induce splenocytes to secrete IFN-g. The bDNA-indirect interaction with cells of the immune system duced IFN-g response was strictly macrophage depen-(such as macrophages) or by the release of soluble medident. While splenocytes from SCID mice secreted IFNators (such as endotoxin or enterotoxin) which induce g in response to bDNA, depletion of macrophages elimhost cytokine production. Bacterial DNA is known to inated this response. Additionally, purified NK cells activate B cells (16, 17) and has been shown to induce did not respond to bDNA; however, addition of macro-IFN-g production in vitro and in vivo (18, 19). Additionphages restored the NK cell IFN-g response. Coculture ally, the efficacy of DNA-based immunization is markof NK cells with preactivated macrophages further inedly enhanced by the presence of immunostimulatory creased bDNA-induced NK cell IFN-g production. Anti-CpG motifs within the immunizing vector (20). Our IL-12 or IL-10 inhibited bDNA-induced IFN-g response. Treatment of purified macrophages with bDNA re-laboratory has examined the proinflammatory propersulted in IL-12 secretion accompanied by an increase ties of bacterial DNA (bDNA), and we previously in IL-12 p40 mRNA level. Although isolated NK cells showed that bDNA functioned as a potent stimulator did not make IFN-g in response to bDNA, NK cells coof in vivo IFN-g production by NK cells (but not T cells). stimulated with IL-12 gained the ability to respond to In vivo exposure to as little as 30 mg of bDNA also bDNA. These experiments show that bDNA induces markedly augmented the toxicity of endotoxin (21). To macrophage IL-12 production which, in turn, stimubegin to unravel the mechanism by which bDNA inlates NK cell IFN-g production. Macrophage-derived duces cytokine production, we have examined cellular IL-12 renders NK cells responsive to bDNA permitting interactions responsible for the host response to bDNA. an even greater IFN-g response to bDNA. ᭧ 1997 Academic We examined the in vitro response of defined lymphoid Press populations to bDNA, and, unexpectedly, we found that isolated NK cells do not secrete IFN-g following challenge with bDNA. However, NK cells do produce IFN-185
Journal of Leukocyte Biology, 2005
Salmonella enterica serovar typhimurium (S. typhimurium) is an intracellular pathogen causing localized gastroenteritis in humans. Macrophages (Mphis) and dendritic cells (DCs) play an important role in innate immunity against Salmonella. In this report, we have compared the consequences of infection of human Mphis and DCs with wild-type S. typhimurium and an isogenic PgtE-defective strain. PgtE is an outer membrane protein hypothesized to have a role in intracellular survival of Salmonella. We observed that DCs undergo full maturation in response to Salmonella infection, as indicated by up-regulation of cell-surface marker proteins CD80, CD83, CD86, and human leukocyte antigen class II. CC chemokine ligand 5 (CCL5), CXC chemokine ligand 10, tumor necrosis factor alpha, interleukin (IL)-12, and IL-18 gene expression and protein production were readily induced by Salmonella-infected Mphis and DCs. CCL20 was preferentially produced by Mphis, whereas DCs secreted higher levels of CCL19 as compared with Mphis. DCs and Mphis infected with S. typhimurium also produced high levels of interferon-gamma (IFN-gamma). Cytokine neutralization and stimulation experiments suggest that the production was partly regulated by Salmonella-induced type I IFNs, IL-12, and IL-18. DC cytokine production induced by Salmonella was much higher as compared with the responses induced by Salmonella lipopolysaccharide or flagellin. Mphis and DCs were capable of internalizing and harboring Salmonella for several days. S. enterica PgtE provided no survival advantage for the bacteria in human Mphis or DCs. Our results demonstrate that although Mphis and DCs share similar functions, they may have different roles during Salmonella infection as a result of differential production of certain chemokines and cytokines.