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A new self: MHC-class-I-independent Natural-killer-cell self-tolerance

Nature Reviews Immunology volume 5, pages 363–374 (2005)Cite this article

Key Points

  • Natural killer (NK) cell cytotoxicity is regulated by inhibitory receptors that bind self-MHC class I molecules. The absence of MHC class I expression causes lysis of cells, as described by the 'missing-self' hypothesis.

  • Some aspects of NK-cell biology cannot be explained by the regulation of self-tolerance through MHC class I molecules alone, implying the existence of non-MHC-binding inhibitory receptors.

  • 2B4 is a prototypical MHC-independent inhibitory receptor. It inhibits NK-cell responses to CD48-expressing cells in mice, as well as in the absence of SAP (signalling lymphocytic activation molecule (SLAM)-associated protein) in humans. This inhibition protects against NK-cell autoreactivity.

  • Carcinoembryonic-antigen-related cell-adhesion molecule 1 (CEACAM1) ensures NK-cell tolerance in MHC-class-I-deficient humans.

  • Several other NK-cell inhibitory receptors recognize diverse ligands that are markers of 'self'. These receptors include some NK-cell receptor protein 1 (NKR-P1)-family members, sialic-acid-binding immunoglobulin-like lectins (SIGLECs) and glycoprotein 49 B1 (gp49B1).

  • Non-MHC-binding inhibitory receptors regulate NK-cell responses in disease states, including infection, cancer and autoimmunity. These receptors might provide new targets for improving NK-cell responses, possibly leading to better treatments for such diseases.

Abstract

A fundamental tenet of the immune system is the requirement for lymphocytes to respond to transformed or infected cells while remaining tolerant of normal cells. Natural killer (NK) cells discriminate between self and non-self by monitoring the expression of MHC class I molecules. According to the 'missing-self' hypothesis, cells that express self-MHC class I molecules are protected from NK cells, but those that lack this self-marker are eliminated by NK cells. Recent work has revealed that there is another system of NK-cell inhibition, which is independent of MHC class I molecules. Newly discovered NK-cell inhibitory receptors that have non-MHC-molecule ligands broaden the definition of self as seen by NK cells.

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Figure 1: NK-cell self-tolerance and the 'missing-self' hypothesis.
Figure 2: NK-cell inhibitory receptors that have non-MHC-molecule ligands.
Figure 3: Proximal signalling pathways of 2B4: activating and inhibitory.

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Acknowledgements

We thank A. Abbas, M. Alegre, B. Jabri and R. Taniguchi for helpful comments regarding the manuscript.

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Authors and Affiliations

  1. Department of Pathology, Committee on Immunology, University of Chicago, 5841 South Maryland Avenue, S-315 MC3083, Chicago, 60637, Illinois, USA

    Vinay Kumar & Megan E. McNerney

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  1. Vinay Kumar
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Correspondence to Vinay Kumar.

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DATABASES

2B4

CD47

CD48

CEACAM1

CLR-B

gp49B1

αVβ3-integrin

NKR-P1D

SIGLEC7

SIRP-β2

FURTHER INFORMATION

Vinay Kumar's homepage

Glossary

CENTRAL TOLERANCE

Self-tolerance that is created at the level of the central lymphoid organs. Developing T cells, in the thymus, and developing B cells, in the bone marrow, that strongly recognize self-antigen must undergo further rearrangement of antigen-receptor genes to become self-tolerant, or they face deletion. NK cells, which differentiate in the bone marrow, are thought to upregulate the expression of inhibitory receptors until they are self-tolerant and are allowed to migrate to the periphery.

PERIPHERAL TOLERANCE

Self-tolerance that is mediated in the peripheral tissues. These mechanisms control potentially self-reactive lymphocytes that have escaped central-tolerance mechanisms.

IMMUNORECEPTOR TYROSINE-BASED INHIBITORY MOTIFS

(ITIMs). ITIMs have the amino-acid sequence Ile/Val-X-Tyr-X-X-Leu/Val, where X denotes any amino acid. They recruit inhibitory phosphatases after phosphorylation of their tyrosine residue.

C-TYPE LECTIN

Lectins are carbohydrate-binding molecules, and C-type lectins were named for their ability to bind calcium. C-type- lectin-like molecules, such as many of the natural-killer-cell receptors, are disulphide-linked homodimers that have sequence homology to C-type lectins; however, they do not bind calcium, and they often recognize proteins instead of carbohydrates.

LEADER PEPTIDES

Hydrophobic amino-acid sequences that signal for proteins to translocate to the endoplasmic reticulum. The leader peptide is cleaved before a protein is transported from the cell.

TRANSPORTER ASSOCIATED WITH ANTIGEN PROCESSING

(TAP). TAP1 and TAP2 form a heterodimer in the membrane of the endoplasmic reticulum. The TAP1–TAP2 complex transports peptides from the cytoplasm to the endoplasmic reticulum, where peptides can be loaded onto MHC class I molecules. Without these peptides, MHC class I molecules are unstable and are much less likely to transit to the cell surface or to remain there.

β2-MICROGLOBULIN

(β2m). A single immunoglobulin-like domain that non-covalently associates with the main polypeptide chain of MHC class I molecules. In the absence of β2m, MHC class I molecules are unstable and are therefore found at very low levels at the cell surface.

SIGNALLING LYMPHOCYTIC ACTIVATION MOLECULE

(SLAM). A receptor that is expressed by several types of immune cell. Receptors in the SLAM subfamily of CD2 proteins, which includes 2B4, have similar sequences, have immunoreceptor tyrosine-based switch motifs (ITSMs) and bind SLAM-associated protein (SAP).

IMMUNORECEPTOR TYROSINE-BASED SWITCH MOTIFS

(ITSMs). ITSMs have the amino-acid sequence Thr-X-Tyr-X-X-Val/Ile, where X denotes any amino acid. They recruit many of the same signalling molecules as immunoreceptor tyrosine-based inhibitory motifs (ITIMs) and immunoreceptor tyrosine-based activation motifs (ITAMs), but they also recruit SAP (signalling lymphocytic activation molecule (SLAM)-associated protein).

SRC-HOMOLOGY-2 DOMAIN

(SH2 domain). A domain that is found in signalling molecules. It binds phosphorylated tyrosine residues and thereby mediates protein–protein interactions.

IMMUNORECEPTOR TYROSINE-BASED ACTIVATION MOTIFS

(ITAMs). ITAMs have the amino-acid sequence Asp/Glu-X-X-Tyr-X-X-Leu/Ile-X6–8-Tyr-X-X-Leu/Ile, where X denotes any amino acid. They recruit activating signalling molecules after tyrosine phosphorylation.

X-LINKED LYMPHOPROLIFERATIVE SYNDROME

(XLP). Patients with XLP have complicated immune dysfunctions, often triggered by infection with Epstein–Barr virus. Many patients develop fatal B-cell lymphoproliferation. The gene that encodes SAP (signalling lymphocytic activation molecule (SLAM)-associated protein) has been found to be mutated in these patients.

GLYCOSYLPHOSPHATIDYL-INOSITOL LINKED

(GPI linked). A lipid modification of a protein that anchors the protein to the plasma membrane.

V-SET IMMUNOGLOBULIN DOMAIN

An immunoglobulin domain is a characteristic protein fold that is present in all members of the immunoglobulin superfamily. On the basis of size and sequence, V-set immunoglobulin domains are similar to the variable regions of antibody molecules.

C2-SET IMMUNOGLOBULIN DOMAINS

C2-set immunoglobulin domains are similar to the constant regions of antibody molecules, as defined on the basis of size and sequence.

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Kumar, V., McNerney, M. A new self: MHC-class-I-independent Natural-killer-cell self-tolerance. Nat Rev Immunol 5, 363–374 (2005). https://doi.org/10.1038/nri1603

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