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  • Review Article
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Roles of the NKG2D immunoreceptor and its ligands

Key Points

  • NKG2D is a lectin-like type-2 transmembrane stimulatory immunoreceptor, which contains a charged transmembrane residue that enables it to interact with signalling adaptor molecules.

  • NKG2D is expressed by natural killer (NK) cells, CD8+ T cells, γδ T cells, NK1.1+ T cells and some myeloid cells.

  • NKG2D recognizes several families of ligands, which are distantly related to MHC class I molecules, including the MHC class-I-chain-related protein A (MICA) and MICB encoded in the human MHC, and a diverse family of proteins present in both mice and humans — retinoic acid early transcript 1 (Rae1), H60 and mouse UL16-binding protein-like transcript 1 (Mult1) in mice, and the UL16-binding proteins (ULBPs) or RAET1 proteins in humans. The ligands are related, but have highly diverse sequences.

  • The structures of NKG2D–ligand complexes indicate that NKG2D binds diagonally over the α1 and α2 helices of the ligands, much as T-cell receptors bind over MHC molecules. Furthermore, despite the poor homology of different ligands, some of the key residues that interact with NKG2D are conserved, and the NKG2D residues involved in binding are similar in the different structures.

  • The ligands are generally poorly expressed by normal cells, but are upregulated in transformed, infected and, in some cases, stressed cells.

  • The engagement of NKG2D is a sufficient stimulus to activate cytolysis and cytokine production by NK cells. However, it provides an enhancing or co-stimulatory signal for the activation of CD8+ T cells and probably other T cells.

  • NKG2D associates in most NKG2D+ cells with the signalling adaptor molecule DNAX-activating protein of 10 kDa (DAP10), which can recruit and activate phosphatidylinositol 3-kinase (PI3K) and downstream signalling molecules. DAP10 is required for NKG2D function in CD8+ T cells, but DAP10-deficient mouse NK cells retain marked cytolytic capacity.

  • An alternatively spliced isoform of NKG2D expressed by mouse NK cells and macrophages can associate with DAP12 — a signalling adaptor molecule that recruits and activates SYK and ζ-chain-associated protein 70 kDa (ZAP70) tyrosine kinases. DAP12 is required for normal cytokine production and optimal cytolysis of mouse NK cells.

  • Expression of NKG2D ligands by tumour-cell lines results in effective rejection in vivo by NK cells and in some cases T cells, and induces long-lasting T-cell-mediated immunity to rechallenge with the parental tumour cells lacking expression of the ligands.

  • Expression of NKG2D ligands is upregulated by cells infected with diverse types of pathogen. Certain viral pathogens encode evasion proteins that retain NKG2D ligands intracellularly, and viral mutants that lack these evasion proteins have reduced pathogenicity.

Abstract

According to present concepts, innate immunity is regulated by receptors that determine danger levels by responding to molecules that are associated with infection or cellular distress. NKG2D is, perhaps, the best characterized receptor that is associated with responses to cellular distress, defined as transformation, infection or cell stress. This review summarizes recent findings that concern NKG2D, its ligands, its signalling properties and its role in disease, and provides a framework for considering how the induction of immune responses can be regulated by cellular responses to injury.

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Figure 1: The NKG2D gene and the NKG2D receptor.
Figure 2: The diverse nature of NKG2D ligands.
Figure 3: Domain structures and affinities of various NKG2D ligands.
Figure 4: Comparative roles of Toll-like receptors and NKG2D in immune recognition.
Figure 5: Associations of NKG2D with signalling molecules in mouse natural killer cells.

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Acknowledgements

I am indebted to E. Vivier for carefully reviewing the manuscript and for providing useful insights. Research in my laboratory is supported by the National Institutes of Health and an award from the CAPCure Foundation.

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DATABASES

LocusLink

CCL1

CCL4

CD19

CD28

CD94

DAP10

DAP12

GM-CSF

H60

ICOS

IFN-α

IFN-β

IFN-γ

IL-15

LAT

MICA

MICB

NKG2A

NKG2C

NKG2D

NKG2E

PLC-γ2

Rae1β

RAET1E

SLP76

ULBP3

ZAP70

Further information

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Glossary

IMMUNORECEPTOR TYROSINE-BASED ACTIVATION MOTIF

(ITAM). A short sequence found in the cytoplasmic domains of numerous immune receptors. After receptor engagement, tyrosines in the ITAM are phosphorylated, enabling the recruitment and activation of SYK or ZAP70 protein tyrosine kinases.

REDIRECTED KILLING

An experimental system for determining the capacity of a natural killer (NK)-cell receptor to induce cytotoxicity. NK cells coated with antibody specific for a candidate receptor are assessed for their ability to kill target cells that express an Fc receptor to which the antibody binds.

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Raulet, D. Roles of the NKG2D immunoreceptor and its ligands. Nat Rev Immunol 3, 781–790 (2003). https://doi.org/10.1038/nri1199

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