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  • Review Article
  • Published:

Self-tolerance of natural killer cells

Key Points

  • Natural killer (NK) cells are lymphocytes of the innate immune system. They are significant producers of cytokines such as interferon-γ and can lyse tumour cells, virus-infected cells and transplanted bone-marrow allografts.

  • Similar to other lymphocytes, NK cells achieve tolerance to self. This means that although they can attack self cells, there are specific developmental mechanisms that ensure that this does not normally occur.

  • Recognition and lysis of target cells by NK cells is regulated by the interplay of many stimulatory and inhibitory receptors.

  • Many NK cells are prevented from attacking self cells through the expression of inhibitory receptors specific for self MHC class I molecules. However, recent data strongly indicate that not all NK cells express an inhibitory receptor for self MHC class I molecules.

  • NK cells that fail to express an inhibitory receptor specific for a self MHC class I molecule are hyporesponsive to stimuli provided by self cells. However, the hyporesponsiveness seems to be contextual, because the hyporesponsive population of NK cells can nevertheless mount normal responses to other stimuli, such as cells infected with Listeria monocytogenes.

  • Several mechanisms to account for the tolerance of NK cells have been proposed recently, including an 'arming' model and a 'disarming' model. This Review considers the evidence for and against these models.

Abstract

Natural killer (NK) cells, similar to other lymphocytes, acquire tolerance to self. This means that NK cells have the potential to attack normal self cells but that there are mechanisms to ensure that this does not usually occur. Self-tolerance is acquired by NK cells during their development, but the underlying molecular and cellular mechanisms remain poorly understood. Recent studies have produced important new information about NK-cell self-tolerance. Here, we review the evidence for and against possible mechanisms of NK-cell self-tolerance, with an emphasis on the role of MHC-specific receptors.

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Figure 1: The balance of inhibitory and stimulatory signals received by a natural killer cell determines the outcome of interactions with target cells.
Figure 2: Possible mechanisms leading to natural-killer-cell self-tolerance.
Figure 3: Comparison of arming and disarming as mechanisms of natural-killer-cell self-tolerance.
Figure 4: Contextual hyporesponsiveness.

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Acknowledgements

We thank N. Fernandez, E. Treiner and our other colleagues for discussion and insights concerning NK-cell tolerance, and the National Institutes of Health (United States) for supporting our research.

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Correspondence to David H. Raulet.

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Glossary

Adaptor molecules

Proteins, often without intrinsic biochemical activity, that function mainly to bind one signalling protein and bring it into proximity to another.

Transporter associated with antigen processing 1

(TAP1). A molecule that transports short peptides from the cytosol to the endoplasmic reticulum and is required for normal cell-surface expression of MHC class I molecules.

Anergy

A state of unresponsiveness that is sometimes observed in T and B cells that are chronically stimulated or are stimulated through the antigen receptor in the absence of co-stimulatory signals.

CD4+CD25+ regulatory T cells

A population of T cells that has been shown to regulate the function of other T cells.

Hyporesponsive NK cells

A subset of natural killer (NK) cells in normal animals and all of the NK cells in MHC-class-I-deficient animals show dampened (but not necessarily absent) responses to stimulatory-receptor engagement compared with typical NK cells in normal animals. The term does not imply any mechanism for how these NK cells arise.

Redirected lysis

Lysis that occurs when an Fc-receptor-expressing target cell is coated with antibodies specific for a stimulatory receptor on a cytolytic cell. The antibodies, bound to the target cell through their Fc region, bind the antigen receptor, thereby mimicking antigenic stimulation and triggering lysis of the target cell.

Concanavalin A

(conA). A lectin that activates T cells.

Dominant-negative SHP1

A catalytically inactive version of SRC-homology-2-domain-containing protein tyrosine phosphatase 1 (SHP1; which is encoded by the gene Ptpn6) that still binds the cytoplasmic tail of receptors, thereby blocking the function of wild-type SHP1.

Immunoreceptor tyrosine-based inhibitory motif

(ITIM). A short amino-acid sequence (the consensus sequence of which is V/IXYXXV/L, where X denotes any amino acid) that is found in the cytoplasmic tail of inhibitory receptors. ITIMs are thought to mediate inhibitory signalling by recruiting phosphatases such as SHP1 (SRC-homology-2-domain-containing protein tyrosine phosphatase 1).

Bromodeoxyuridine labelling

(BrdU labelling). A technique in which dividing cells exposed to BrdU incorporate it into their DNA. These cells can be identified by intracellular staining with antibodies specific for BrdU. Non-dividing cells do not incorporate BrdU.

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Raulet, D., Vance, R. Self-tolerance of natural killer cells. Nat Rev Immunol 6, 520–531 (2006). https://doi.org/10.1038/nri1863

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