Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2011 Nov;68(21):3505-18.
doi: 10.1007/s00018-011-0801-8. Epub 2011 Aug 23.

Natural killer cell activation by dendritic cells: balancing inhibitory and activating signals

Rosa Barreira da Silva  1 , Christian Münz
Affiliations
Review

Natural killer cell activation by dendritic cells: balancing inhibitory and activating signals

Rosa Barreira da Silva et al. Cell Mol Life Sci. 2011 Nov.

Abstract

Natural killer (NK) cells have originally been identified by their spontaneous cytolytic potential against tumor cells, which, however, might result from pre-activation due to prior pathogen exposure. Resting NK cells, on the contrary, require activation by bystander antigen-presenting cells to reach their full functional competence. In this review, we will summarize studies on how dendritic cells (DCs), the most potent type of antigen-presenting cell, communicate with human NK cells to activate them in secondary lymphoid organs and to integrate signals from activated NK cells at sites of inflammation for their own maturation. Furthermore, we will review aspects of the immunological synapse, which mediates this cross-talk. These studies provide the mechanistic understanding of how mature DCs can activate NK cells and survive to go on for the activation of adaptive immunity. This feature of DCs, to activate different waves of immune responses, could be harnessed for immunotherapies, including vaccinations.

PubMed Disclaimer

Figures

Fig. 1
Fig. 1
Natural killer cell activation by dendritic cells. Dendritic cells (DCs) patrol the body constantly in their immature stage. 1 Upon recognition of a stress signal, that can be pathogen-derived, necrotic cellular debris or pro-inflammatory cytokines, DCs undergo maturation. Some stress signals are detected by toll-like receptors (TLRs). During maturation, DCs up-regulate chemokine receptors, which allow them to efficiently migrate into secondary lymphoid organs (SLOs). 2 There, mature DCs can encounter autologous resting NK cells. The cross-talk between these cells differs depending on the nature of the maturation stimulus received by the DC and the particular subset of DC. Thus, NK cell activation by mature DCs can be mediated by soluble molecules to different degree. Cytokines like IL-12, IL-18 and IL-2 induce IFN-γ secretion by NK cells. Furthermore, IL-15 signaling induces NK cell proliferation and survival, while type I IFNs increases NK cell cytotoxicity. Although these cytokines can be secreted, their effect, especially when produced at limited concentrations by mature DCs, can be improved through conjugation of DCs and NK cells. Furthermore, the direct cell contact between these two cell types is also important for signals derived from receptor/ligand pairs. Along these lines, NK group 2D (NKG2D), glucocorticoid-induced TNF-receptor-related protein (GITR) and intracellular adhesion protein 1 (ICAM1) were shown to activate NK cells, after interaction with their cognate ligands (NKGD2L, GITRL and lymphocyte function-associated lymphocyte 1 (LFA1), respectively) on mature DCs. 3 Even so this cross-talk enhanced NK cell cytotoxicity, DCs survive this interaction due to the high expression of MHC class I molecules after maturation, the presence of inhibitors of granzyme B-mediated apoptosis in mature DCs, and actin-mediated stabilization of NK cell inhibitory signaling by MHC class I molecules at the immunological synapse
Fig. 2
Fig. 2
The immunological synapse between mature dendritic cells and resting natural killer cells. Upon encounter, dendritic cells (DCs) and natural killer (NK) cells rapidly form conjugates, forming an immunological synapse (IS). The IS between mature DCs and resting NK cells has both activating and inhibitory features and can, therefore, be described as a regulatory synapse. The immature IS between DCs and NK cells (formed after 1–5 min of interaction) presents enrichment of both activating [IL-15R, talin, lymphocyte function associated molecule 1 (LFA-1)] and inhibitory [killer cell immunoglobulin like receptors (KIRs), CD94 and MHC class I] molecules at the IS (left side). The parallel signaling of these opposing interactions is possible due to the spatial separation of activating and inhibitory domains in the IS, which cluster IL-15R, MHC class I, KIRs and CD94 molecules in the central part of the IS and are surrounded by talin and LFA-1 molecules. Upon maturation of the synapse (after 15–20 min of interaction), DCs-derived filamentous actin polymerized at the interface between the cells (right side). Furthermore, IL-12 and IL-12R accumulate at the IS, while IL-15R and MHC class I polarization to the synapse is maintained. The maintenance of inhibitory signaling via MHC class I prevents polarization of the cytolytic machinery, like perforin-containing granules and the microtubule organizing center (MTOC), to the synapse. The synchronized signaling of activating and inhibitory molecules allows NK cell activation and inhibition of DC lysis by NK cells at the same time. Microscopy pictures represent conjugates between poly(I:C) matured DCs and autologous resting NK cells after 1 (left) and 20 min (right) of co-culture. Filamentous actin (green) and nuclear DNA (blue) were stained. Original magnifications ×100, scale bars 10 μm
Fig. 3
Fig. 3
Dendritic cell editing: killing, maturation, and Th1 polarization by natural killer cells. Sites of inflammation allow activated natural killer (NK) cells to encounter immature dendritic cells (DCs). 1 At high NK cell/DC ratios, NK cells can kill immature DCs, due to the engagement of the natural cytotoxicity receptors p30 and p46 and DNAX accessory molecule 1 (NKp30, NKp46 and DNAM-1). The low levels of HLA-E expression on immature DCs are unable to inhibit this NK cell activation. It is thought that cytotoxic editing of DCs by NK cell is mediated by TRAIL/DR4/5-induced apoptosis. 2 At low NK/DC ratios, NK cells can promote maturation of DCs, via type II interferon, tumor necrosis factor and granulocyte macrophage colony-stimulating factor (IFN-γ, TNF and GM-CSF, respectively). These cytokines induce phenotypic maturation of DCs, which includes up-regulation of co-stimulatory and MHC molecules (CD83, CD86, MHC class I and MHC class II). Furthermore, in some cases, cytokine production by DCs is also induced (like IL-12 secretion). Maturation of DCs enables then to migrate into secondary lymphoid organs (SLOs), due to the upregulation of chemokine receptors, like C–C chemokine receptor 7 (CCR7). 3 Inside SLOs, DCs previously activated by NK cells were found to efficiently prime protective adaptive responses, including Th1 polarization of naïve CD4+ T cells and cytotoxic responses by CD8+ T cells
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature. 1998;392:245–252. - PubMed
    1. Ferlazzo G, et al. Distinct roles of IL-12 and IL-15 in human natural killer cell activation by dendritic cells from secondary lymphoid organs. Proc Natl Acad Sci USA. 2004;101:16606–16611. - PMC - PubMed
    1. Caux C, Massacrier C, Vanbervliet B, Dubois B, Van Kooten C, Durand I, Banchereau J. Activation of human dendritic cells through CD40 cross-linking. J Exp Med. 1994;180:1263–1272. - PMC - PubMed
    1. Cella M, Scheidegger D, Palmer-Lehmann K, Lane P, Lanzavecchia A, Alber G. Ligation of CD40 on dendritic cells triggers production of high levels of interleukin-12 and enhances T cell stimulatory capacity: T–T help via APC activation. J Exp Med. 1996;184:747–752. - PMC - PubMed
    1. Reis e Sousa C, Hieny S, Scharton-Kersten T, Jankovic D, Charest H, Germain RN, Sher A. In vivo microbial stimulation induces rapid CD40 ligand-independent production of interleukin 12 by dendritic cells and their redistribution to T cell areas. J Exp Med. 1997;186:1819–1829. - PMC - PubMed

Publication types

MeSH terms

LinkOut - more resources