Natural Killer Dendritic Cells Have Both Antigen Presenting and Lytic Function and in Response to CpG Produce IFN- via Autocrine IL-12 (original) (raw)
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The Journal of Immunology, 2005
We have isolated rare cells bearing the NK cell surface marker NK1.1, as well as the dendritic cell (DC) marker CD11c, from the spleen, liver, lymph nodes, and thymus of normal mice. These cells possess both NK cell and DC function because they can lyse tumor cells and subsequently present Ags to naive Ag-specific T cells. Interestingly, in response to IL-4 plus either IL-2 or CpG, NKDC produce more IFN-γ than do DC, or even NK cells. We determined that CpG, but not IL-2, induces NKDC to secrete IFN-γ via the autocrine effects of IL-12. In vivo, CpG dramatically increases the number of NKDC. Furthermore, NKDC induce greater Ag-specific T cell activation than do DC after adoptive transfer. Their unique ability to lyse tumor cells, present Ags, and secrete inflammatory cytokines suggests that NKDC may play a crucial role in linking innate and adaptive immunity.
BMC Immunology, 2018
Background: Besides their prominent role in the elimination of infected or malignantly transformed cells, natural killer (NK) cells serve as modulators of adaptive immune responses. Enhancing bidirectional crosstalk between NK cells and dendritic cells (DC) is considered a promising tool to potentiate cancer vaccines. We investigated to what extent direct sensing of viral and bacterial motifs by NK cells contributes to the response of inflammatory DC against the same pathogenic stimulus. Results: We demonstrated that sensing of bacterial and viral PAMPs by NK cells contributes to DC cytokine production via NK cell-derived soluble factors. This enhancement of DC cytokine production was dependent on the pattern recognition receptor (PRR) agonist but also on the cytokine environment in which NK cells recognized the pathogen, indicating the importance of accessory cell activation for this mechanism. We showed in blocking experiments that NK cell-mediated amplification of DC cytokine secretion is dependent on NK cell-derived IFN-γ irrespective of the PRR that is sensed by the NK cell. Conclusions: These findings illustrate the importance of bidirectional interaction between different PRR-expressing immune cells, which can have implications on the selection of adjuvants for vaccination strategies.
The dialogue between natural killer cells and dendritic cells
International Congress Series, 2005
Natural killer (NK) cells play an important role in the early innate response against cancer and infections whereas dendritic cells (DC) are critical in the initiation of adaptive immune responses through their unique antigen presentation capacities. It was discovered in 1999 by Fernandez et al. that DC and NK cells make functional interactions. In vitro, IL-12/IL-18, IL-15 and IFN-a/h production by activated DC enhance NK cell IFN-g production, proliferation and cytotoxic potential, respectively. Activated NK cells induce DC maturation either directly or in synergy with suboptimal levels of microbial signals. NK cell-induced DC activation is dependent on both TNF-a/IFN-g secretion and a cell-cell contact. Finally, immature DC appear susceptible to autologous NK cellmediated cytolysis while mature DC are protected. Thus, the outcome of NK/DC cross-talk is likely to influence both innate and adaptive immune responses. In vivo, NK/DC interactions occur at least in lymphoid organs and promote Th1 differentiation. Thus, DC and NK cells are equipped with complementary sets of receptors that allow the recognition of various pathogenic agents, rendering the cross-talk between the two partners mandatory. D 2005 Published by Elsevier B.V.
A Contribution of Mouse Dendritic Cell-Derived IL-2 for NK Cell Activation
Journal of Experimental Medicine, 2004
Dendritic cells (DCs) play a predominant role in activation of natural killer (NK) cells that exert their functions against pathogen-infected and tumor cells. Here, we used a murine model to investigate the molecular mechanisms responsible for this process. Two soluble molecules produced by bacterially activated myeloid DCs are required for optimal priming of NK cells. Type I interferons (IFNs) promote the cytotoxic functions of NK cells. IL-2 is necessary both in vitro and in vivo for the efficient production of IFN ␥ , which has an important antimetastatic and antibacterial function. These findings provide new information about the mechanisms that mediate DC-NK cell interactions and define a novel and fundamental role for IL-2 in innate immunity.
Interleukin-12 secreted by mature dendritic cells mediates activation of NK cell function
FEBS Letters, 2004
Dendritic cells (DCs) are known to modulate immune response by activating e¡ector cells of both the innate and the adaptive immune system. In the present study, we demonstrate that co-culture of DCs with paraformaldehyde-¢xed tumor cells augments the secretion of interleukin (IL)-12 by DCs and these activated DCs upon co-culture with naive NK cells enhance the cytolytic activity of NK cells against NK-sensitive target YAC-1. Similarly, DCs isolated from tumor-bearing animals also activated NK cells in vitro. For e⁄cient activation of NK cells, the ratio of activated DCs to NK cells is crucial. Addition of anti-IL-12 antibody to the culture system completely abolished activation of NK cells by DCs, suggesting that IL-12 secreted by DCs is an essential factor in NK cell activation. Adoptive transfer of DCs isolated from tumor-bearing animals into normal rats also induced activation of NK cells in normal animals.
Cancer Research, 2009
IFN-producing killer dendritic cells (IKDC) represent a recently discovered cell type in the immune system that possesses a number of functions contributing to innate and adaptive immunity, including production of type 1 and 2 IFNs, interleukin (IL)-12, natural killing, and ultimately antigen presentation to naïve T cells. Here, we compared in vitro and in vivo responses of mouse IKDC, conventional dendritic cells (DC), and natural killer (NK) cells to murine cytomegalovirus infection and found distinct functions among these cell subsets. Upon recognition of infected fibroblasts, IKDC, as well as NK, produced high level of IFN-;, but unlike NK, IKDC simultaneously produced IL-12p40 and up-regulated MHC class II (MHC-II) and costimulatory molecules. Using MHC-II molecule expression as a phenotypic marker to distinguish activated IKDC from activated NK, we further showed that highly purified MHC-II + IKDC but not NK cross-present MHC class I-restricted antigens derived from MCMV-infected targets to CD8 + T cells in vitro and in vivo. Our findings emphasize the unique nature of IKDC as a killer antigenpresenting cell directly linking innate and adaptive immunity.
Journal of Experimental Medicine, 2007
In this study, we examine the lytic function and antigen-presenting capacity of mouse spleen IKDCs, including those found in DC preparations. IKDCs effi ciently killed NK cell targets, without requiring additional activation stimuli. However, in our hands, when exposed to protein antigen or to MHC class II peptide, IKDCs induced little or no T cell proliferation relative to conventional DCs or plasmacytoid DCs, either before or after activation with CpG, or in several disease models. Certain developmental features indicated that IKDCs resembled NK cells more than DCs. IKDCs, like NK cells, did not express the transcription factor PU.1 and were absent from recombinase activating gene-2 -null, common ␥ -chainnull (Rag2 ؊ / ؊ Il2rg ؊ / ؊ ) mice. When cultured with IL-15 and -18, IKDCs proliferated extensively, like NK cells. Under these conditions, a proportion of expanded IKDCs and NK cells expressed high levels of surface MHC class II. However, even such MHC class II ؉ IKDCs and NK cells induced poor T cell proliferative responses compared with DCs. Thus, IKDCs resemble NK cells functionally, and neither cell type could be induced to be effective antigen-presenting cells.