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Natural killer cells, viruses and cancer

Key Points

  • Natural killer (NK) cell function (cytotoxic activity and cytokine secretion) is regulated by a balance of signals transmitted by opposing activating and inhibitory receptors.

  • Activating NK cell receptors use transmembrane adaptor proteins such as FcɛRIγ, CD3ζ and DAP12 to stimulate the ZAP70 and Syk tyrosine kinase pathways, and another transmembrane adaptor protein DAP10 to activate the phosphatidylinositol 3-kinase pathway.

  • The activating NKG2D receptor binds to human major histocompatibility complex (MHC) class-I-chain-related A (MICA) and MICB proteins, encoded by genes within the MHC, and to glycoproteins that represent orthologues of the mouse retinoic acid early inducible (RAE-1) molecules.

  • NK cells kill tumours expressing the MIC or RAE-1 ligands of the NKG2D receptor, even when the tumours express MHC class I molecules that are recognized by the inhibitory NK cell receptors.

  • A role of NK cells in anti-viral immunity has been demonstrated most convincingly in protection against cytomegalovirus and other herpesviruses.

  • Infection with human cytomegalovirus induces expression of MIC proteins, ligands of the activating NKG2D receptor.

  • The mouse activating Ly49H receptor has been implicated in host resistance to mouse cytomegalovirus.

  • Cytomegalovirus encodes several proteins that bind to MHC class I and MIC that might inhibit recognition by T cells and NK cells.

Abstract

Natural killer cells are innate immune cells that control certain microbial infections and tumours. The function of natural killer cells is regulated by a balance between signals transmitted by activating receptors, which recognize ligands on tumours and virus-infected cells, and inhibitory receptors specific for major histocompatibility complex class I molecules. Here, we review the emerging evidence that natural killer cells have an important role in vivo in immune defence.

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Figure 1: Activating NK receptor complexes.
Figure 2: NKG2D ligands and HCMV.
Figure 3: Ly49H and mouse cytomegalovirus (MCMV).
Figure 4: NKG2D ligands in innate tumour surveillance.

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Acknowledgements

This work was supported by grants from the National Institutes of Health. We thank R. Welsh, W. Yokoyama, S. Bahram and R. Strong for helpful discussions and sharing unpublished manuscripts.

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DATABASE LINKS

LocusLink

CD2

CD3ζ

CD16

CD28

CD48

CD54

CD58

CD69

CD84

CD86

CD150

CD159a

CD244

Cmv1

DAP10

DAP12

H60

HLA-A

HLA-B

HLA-C

HLA-E

ICOS

IFN-α

IFN-β

IFN-γ

IL-2

IL-10

KIR

KIR2DS

LFA-1

LIR-1

Ly9

Ly49

Ly49H

lymphotoxin-α

lymphotoxin-β

MICA

MICB

NKG2D

NKp30

NKp44

NKp46

p52

Rae-1

SAP

SLAM

TAP

TGF-β

TNF-α

Tyrobp

ULBP1

ULBP2

ULBP3

OMIM

Nasu–Hakola disease

X-linked lymphoproliferative syndrome

FURTHER INFORMATION

AIDS Information & Research

Official List of Human MIC and HLA Antigens

Protein Reviews on the Web, the KIR Family

The World of Human Cytomegalovirus

Glossary

NATURAL KILLER T CELLS

(NKT cells). A subset of T lymphocytes expressing both NK and T-cell markers. In mice, NKT cells were first identified by their expression of the NK1.1 (NKR-P1C) alloantigen. Some mouse NKT cells express an invariant T-cell receptor (TCR) using the Vα14 variable region of the TCR-α chain and recognize CD1d-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 IFN-γ and IL-4.

γδ-TCR+ T CELLS

T lymphocytes express either a T-cell receptor (TCR) composed of either α- and β-subunits (αβ-TCR) or a TCR composed of γ- and δ-subunits (γδ-TCR). Most (>90%) T cells have a αβ-TCR that recognizes conventional MHC class I or II ligands. T cells expressing γδ-TCR are less frequent and the ligands of this type of receptor are less well characterized.

UL16-BINDING PROTEINS

(ULBP). A family of human glycoproteins with homology to MHC class I that was discovered by their ability to bind to UL16, a protein encoded by human cytomegalovirus. The ULBP proteins also serve as ligands for the NKG2D receptor. The mouse orthologues of the ULBP molecules are the retinoic acid early inducible 1 (RAE-1) genes.

ORTHOLOGUES

Homologous genes in different species, the lineages of which derive from a common ancestral gene without gene duplication or horizontal transmission.

MICROARRAY ANALYSIS

A technique for measuring the transcription of genes. It involves hybridization of fluorescent-labelled cDNA prepared from a cell or tissue of interest with glass slides or other surfaces dotted with thousands of oligonucleotides or cDNA, ideally representing all expressed genes in the species.

NASU–HAKOLA DISEASE

Also known as PLOSL (polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy), it is a recessively inherited disease characterized by a unique combination of psychotic symptoms rapidly progressing to presenile dementia and bone cysts restricted to wrists and ankles. It is caused by a loss-of-function mutation in the DAP12 (Tyrobp) gene.

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Cerwenka, A., Lanier, L. Natural killer cells, viruses and cancer. Nat Rev Immunol 1, 41–49 (2001). https://doi.org/10.1038/35095564

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