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  • Review Article
  • Published:

Close encounters of different kinds: Dendritic cells and NK cells take centre stage

Nature Reviews Immunology volume 5, pages 112–124 (2005)Cite this article

Key Points

  • Dendritic cells (DCs) have historically been classified as professional antigen-presenting cells, which monitor their environment for foreign substances that they then internalize, process and present to antigen-specific T cells. More recently, it has become clear that DCs can also interact with natural killer (NK) cells.

  • NK cells are mainly known as efficient executioners. They quickly and efficiently kill tumours and virally infected cells, and although they cannot mount a recall response, they provide an important first line of immune surveillance.

  • Recently, it has become clear that complex bidirectional interactions occur between DCs and NK cells. These interactions are crucial in defining the initiation, progression and outcome of immune responses.

  • DCs regulate the proliferation and activation of NK cells through interactions that require both cell-surface molecules and cytokines. Reciprocally, NK cells influence DC-mediated responses, by causing either DC elimination or DC maturation.

  • The outcome of DC–NK-cell interactions is crucially dependent on the stimuli received, the site where the interactions occur and the cell surface and cytokine signals that are delivered.

  • In a model of cytomegalovirus infection, DC–NK-cell crosstalk has been shown to affect the outcome of antiviral immunity.

  • Similarly, DC–NK-cell interactions are likely to be important in antitumour immunity and can have an impact on NK-cell responses, as well as on adaptive T-cell responses.

  • A better understanding of the bidirectional crosstalk that occurs between DCs and NK cells will bring us closer to the development of more effective immunotherapies for cancer and infection.

Abstract

Immune responses are generally divided into innate and adaptive responses, and the efficacy of one is thought to be independent of the other. The regulation of immune responses, however, is complex, and accumulating evidence indicates that multiple interactions between immune effector cells are common and are crucial for the initiation, as well as the outcome, of these responses. Dendritic cells, long recognized as key initiators of primary adaptive immunity, are now also seen as crucial regulators of aspects of innate immunity, in particular natural-killer-cell function. Reciprocally, natural killer cells can influence the activity of dendritic cells. Here, we review recent exciting progress in this field, and we highlight the impact of this cellular crosstalk on the design of immune-based therapies for control of infection and cancer.

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Figure 1: Interplay between dendritic cells and other immune effectors.
Figure 2: Outcomes of interactions between dendritic cells and natural killer cells.
Figure 3: Crosstalk between dendritic cells and natural killer cells during viral infection.
Figure 4: Impact of crosstalk between dendritic cells and natural killer cells on immunity to tumours.

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Acknowledgements

We are especially grateful to D. Andrews and C. Andoniou from the laboratory of M.A.D.E. for their ongoing contributions to understanding the relevance of DC–NK-cell interactions in viral immune surveillance, and to M. Wallace from the M.J.S. laboratory for discussions concerning DC–NK-cell crosstalk. Other members of our laboratories are also thanked for their contributions and valuable scientific discussions. Research undertaken in our laboratories is supported by grants from the National Health and Medical Research Council (NHMRC) of Australia, the Wellcome Trust (United Kingdom) and the Human Frontier Science Program (France). M.A.D.E. is supported by a Wellcome Trust Overseas Senior Research Fellowship in Biomedical Science. M.J.S. is supported by a Research Fellowship and Program Grant from the NHMRC. We apologize to those colleagues whose work has only been referenced indirectly through reviews as a result of space limitations.

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Authors and Affiliations

  1. Immunology and Virology Program, Centre for Ophthalmology and Visual Science, The University of Western Australia, 6009, Western Australia, Australia

    Mariapia A. Degli-Esposti

  2. Centre for Experimental Immunology, Lions Eye Institute, 2 Verdun Street, Nedlands, 6009, Western Australia, Australia

    Mariapia A. Degli-Esposti

  3. Cancer Immunology Program, Sir Donald and Lady Trescowthick Laboratories, Peter MacCallum Cancer Centre, East Melbourne, 3002, Victoria, Australia

    Mark J. Smyth

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Correspondence to Mariapia A. Degli-Esposti.

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DATABASES

Entrez Gene

CD40

CD80

CD86

IFN-α

IFN-β

IFN-γ

IL-12

MICA

MICB

NKp30

TNF

Glossary

NKT CELLS

(Natural killer T cells). A heterogeneous subset of T cells, most of which express semi-invariant T-cell receptors. In mice, NKT cells were first identified by their expression of the cell-surface molecule NK1.1 (also known as NKR-P1C).

CROSSTALK

The bidirectional interactions between two cell types. Crosstalk refers to the delivery of information and signals from cell population one to cell population two and vice versa. It might involve signals that are mediated by cell–cell contact or by soluble factors, such as cytokines. The signals that are received by each population affect its functions.

TOLL-LIKE RECEPTOR

(TLR). A member of a family of receptors that recognize conserved molecular patterns that are unique to microorganisms. The lipopolysaccharide component of bacterial cell walls is one such component. Stimulation through TLRs induces the maturation of dendritic cells, leading to the optimal activation of the adaptive immune response. TLR-mediated events signal to the host that a microbial pathogen has been encountered.

TH1 CELL

(T helper 1 cell). At least two distinct subsets of activated CD4+ T cells have been described. TH1 cells produce interferon-γ and tumour-necrosis factor and support cell-mediated immunity. TH2 cells produce interleukin-4 (IL-4), IL-5 and IL-13, support humoral immunity and downregulate TH1-cell responses.

ANTIBODY-DEPENDENT CELLULAR CYTOTOXICITY

(ADCC). A mechanism by which natural killer (NK) cells are targeted to IgG-coated cells, resulting in the lysis of the antibody-coated cells. A specific receptor for the constant region of IgG, known as FcγRIII (CD16), is expressed at the surface of NK cells and mediates ADCC.

MURINE CYTOMEGALOVIRUS

(MCMV). A member of the herpesvirus family that is often used as a model of a persistent viral infection. It causes an immune response that limits viral replication; however, the pathogen is not completely eliminated, and it establishes life-long persistence within its host. MCMV has considerable sequence homology and shares biological features with human CMV, and it provides a unique model to study in vivo infection in a natural host.

IMMUNOLOGICAL SYNAPSE

A region that can form between two cells of the immune system in close contact, so named because of its similarities to the synapses that occur in the nervous system. The immunological synapse originally referred to the interaction between a T cell and an antigen-presenting cell. It involves adhesion molecules, as well as antigen receptors and cytokine receptors.

NKG2D

(Natural-killer group 2, member D). A primary activation receptor encoded by the natural killer (NK)-cell gene complex and expressed by all mature NK cells. It recognizes distinct families of ligands that are generally expressed only by infected, stressed or transformed cells.

CD94–NKG2A

(CD94–natural-killer group 2, member A). A natural killer (NK)-cell receptor complex that consists of the invariant molecule CD94 and the C-type lectin receptor NKG2A. This complex delivers inhibitory signals to NK cells after recognition of the non-classical MHC molecule Qa-1b, in mice, or HLA-E, in humans.

DANGER SIGNALS

Cell-wall components and other products of pathogens that alert the innate immune system to the presence of potentially harmful invaders, usually by interacting with Toll-like receptors and other pattern-recognition receptors that are expressed by tissue cells and dendritic cells.

CpG SEQUENCES

Oligodeoxynucleotide sequences that include a cytosine-guanosine sequence and certain flanking nucleotides. These have been found to induce innate immune responses through interaction with Toll-like receptor 9.

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Degli-Esposti, M., Smyth, M. Close encounters of different kinds: Dendritic cells and NK cells take centre stage. Nat Rev Immunol 5, 112–124 (2005). https://doi.org/10.1038/nri1549

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