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Whatever turns you on: accessory-cell-dependent activation of NK cells by pathogens

Nature Reviews Immunology volume 7, pages 279–291 (2007)Cite this article

Key Points

  • Natural killer (NK)-cell activation by most pathogens is strictly dependent on the presence of accessory cells, such as monocytes, macrophages or dendritic cells.

  • Direct contact with accessory cells is required for optimal NK-cell responses to most pathogens, and the molecular interactions that underlie this are beginning to be unravelled.

  • Multiple accessory-cell-derived cytokines — both pro-inflammatory and anti-inflammatory — influence NK-cell responses to pathogens.

  • The precise identity of the accessory cell that mediates NK-cell activation varies from one class of pathogen to another, depending on which accessory cell expresses the appropriate pathogen-recognition receptors for the different classes of pathogen-derived ligands.

  • NK cells can pass reciprocal activating signals to accessory cells; however, the physiological relevance of such bidirectional interactions might depend on the nature, and site, of the infection.

Abstract

Natural killer (NK) cells have a crucial role in combating infections and cancers and their surface receptors can directly recognize and respond to damaged, transformed or non-self cells. Whereas some virus-infected cells are recognized by this same route, NK-cell responses to many pathogens are triggered by a different mechanism. Activation of NK cells by these pathogens requires the presence of accessory cells such as monocytes, macrophages and dendritic cells. Recent studies have identified numerous pathogen-recognition receptors that enable accessory cells to recognize different pathogens and subsequently transmit signals — both soluble and contact-dependent — to NK cells, which respond by upregulating their cytotoxic potential and the production of inflammatory cytokines.

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Figure 1: Interactions of NK cells, accessory cells and pathogens.
Figure 2: Signals passed from accessory cells to NK cells.
Figure 3: Accessory-cell-dependent NK-cell activation by diverse pathogens.

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Acknowledgements

Work on NK cells in the authors' laboratory is financed by the UK Medical Research Council.

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  1. Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, UK

    Kirsty C. Newman & Eleanor M. Riley

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Glossary

γδ T cells

T cells express either a T-cell receptor (TCR) composed of α- and β-subunits (αβ-TCR) or a TCR composed of γ- and δ-subunits (γδ-TCR). Most human T cells (more than 90%) express αβ-TCRs that mainly recognize antigenic peptides bound to conventional MHC class I or II molecules. T cells that express γδ-TCRs are less abundant, and the ligands for these receptors are less well characterized.

Natural killer T cells

(NKT cells). A subset of T cells expressing both NK and T-cell markers. In mice, NKT cells were first identified by their expression of the NK1.1 (natural-killer-cell-associated antigen 1.1) alloantigen in addition to CD3. Some mouse NKT cells express an invariant T-cell receptor (TCR) using the Vα14 variable region of the TCR α-chain and recognize CD1 d-associated antigen. Similarly, human NKT cells express an invariant Vα24 receptor. NKT cells are characterized functionally by cytolytic activity and rapid production of cytokines, including IFNγ and IL-4.

Accessory cell

A cell that provides contact-mediated or cytokine-mediated signals to other cells of the immmune system, thereby facilitating and regulating their response. These cells are typically professional antigen- presenting cells (APCs), such as dendritic cells (DCs), monocytes or macrophages, however, alternative cell types (including non-immune cells) can also function as accessory cells.

CpG motif

A deoxycytosine–deoxyguanosine sequence. Such sequences are prevalent in bacterial DNA but are rare in mammalian DNA. Unmethylated CpG is endocytosed by cells of the innate immune system and interacts with Toll-like receptor 9, activating a signalling cascade that results in the production of pro-inflammatory cytokines.

Pathogen-associated molecular patterns

(PAMPs). Molecular patterns that are found in pathogens but not in mammalian cells. Examples include terminally mannosylated and polymannosylated compounds (which bind the mannose receptor) and various microbial components, such as bacterial lipopolysaccharide, hypomethylated DNA, flagellin and double-stranded RNA.

Pattern-recognition receptor

(PRR). A host receptor (such as Toll-like receptors or NOD-like receptors) that can sense pathogen-associated molecular patterns and initiate signalling cascades that lead to an innate immune response. These can be membrane bound (e.g. TLRs) or soluble cytoplasmic receptors (e.g. RIG-I, MDA5, NLRs).

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Newman, K., Riley, E. Whatever turns you on: accessory-cell-dependent activation of NK cells by pathogens. Nat Rev Immunol 7, 279–291 (2007). https://doi.org/10.1038/nri2057

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