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  • Review Article
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Inhibitory NK-cell receptors on T cells: witness of the past, actors of the future

Nature Reviews Immunology volume 4, pages 190–198 (2004)Cite this article

Key Points

  • MHC class I molecules can interact with the T-cell receptor complex, CD8 dimers as well as with inhibitory MHC class I receptors. These inhibitory MHC class I receptors belong to the immunoglobulin-like family in humans — killer cell immunoglobulin-like receptors (KIRs) and leukocyte immunoglobulin-like receptors (LIRs) — or to the lectin-like family in mice (Ly49 molecules) or in both species (CD94/NKG2A). They were initially described on natural killer (NK) cells, and also include killer cell lectin-like receptor subfamily G1 (KLRG1), to form a group of inhibitory NK-cell receptors (iNKRs).

  • iNKRs can be expressed by memory phenotype CD8+αβ-T-cell receptor (αβ-TCR)+ T cells, where they increase the threshold of activation leading to the fine tuning of T-cell effector function (cytotoxicity and cytokine secretion). The negative control mediated by iNKRs on T cells is not absolute, but rather varies with the strength of T-cell stimulation as well as the T-cell activation status.

  • iNKRs can also antagonize activation-induced cell death, leading to the survival of T-cell subsets.

  • The cell-surface expression of iNKRs correlates with various stages of CD8+ T-cell differentiation. The HLA-E-specific receptor complex CD94/NKG2 can be readily expressed at the T-cell surface after antigenic challenge, whereas KIR and Ly49 expression is restricted to T-cell subsets with an effector/effector-memory phenotype.

  • The role of iNKRs in NK-cell self-tolerance prompts the future exploration of iNKRs in the control of peripheral T-cell tolerance.

Abstract

Inhibitory MHC class I receptors were initially described on natural killer (NK) cells, where they participate in inducing NK-cell self-tolerance. Inhibitory NK-cell receptors (iNKRs) can also be expressed by diverse T-cell subsets, including NKT cells, CD8+αβ-T-cell receptor (αβ-TCR)+ T cells, CD4+αβ-TCR+ T cells and γδ-TCR+ T cells. Here, we review the factors and the differentiation programme associated with the expression of iNKRs by αβ-TCR+ T cells, as well as the consequences of iNKR expression on T-cell function. A selective model for the induction of iNKR+ T cells is discussed, based on the stochastic expression of various iNKRs by the progeny of a single T-cell clone.

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Figure 1: Inhibitory natural-killer-cell receptors expressed by T-cell subsets.
Figure 2: Signalling pathways initiated by killer cell immunoglobulin-like receptors (KIRs) in T cells.
Figure 3: Hypothetical selective model of KIR+ T-cell induction.

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Acknowledgements

We thank L. Brossay (Brown University), S. Ugolini (CIML), A. Venet (Kremlin-Bicêtre) and D. Raulet (Berkeley) for their advice. E.V. is supported by the INSERM, CNRS and Université de la Méditerranée, as well as by La Ligue Nationale contre le Cancer (Equipe Labellisée “La Ligne”). N.A. is supported by the Ministère de la Recherche and the Association pour la Recherche contre le Cancer.

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  1. Centre d'Immunologie de Marseille-Luminy, INSERM-CNRS-Université de la Méditerranée, Campus de Luminy, case 906, Marseille, 13288 cedex 09, France

    Eric Vivier & Nicolas Anfossi

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  1. Eric Vivier
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  2. Nicolas Anfossi
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Correspondence to Eric Vivier.

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DATABASES

LocusLink

CCR7

CD4

CD8

CD27

CD28

CD34

CD56

CD94

CD95

CD95L

DAP12

HSP60

IFN-γ

IL-2

IL-4

IL-15

IL-21

KIR2DL3

KIR2DL4

KIR3DL2

KLRG1

LIR1

Ly49f

NKG2A

Nkrp1c

PKCα

SHP1

TNF

FURTHER INFORMATION

Eric Vivier's lab

Glossary

IMMUNORECEPTOR TYROSINE-BASED INHIBITORY MOTIF

(ITIM). A structural motif containing tyrosine residues that is found in the cytoplasmic tail of several inhibitory receptors. The prototype six-amino-acid ITIM sequence is (Ile/Val/Leu/Ser)-Xaa-Tyr-Xaa-Xaa-(Leu/Val). Ligand-induced clustering of these inhibitory receptors results in tyrosine phosphorylation, often by SRC-family tyrosine kinases, which provides a docking site for the recruitment of cytoplasmic phosphatases that have an SH2 domain.

IMMUNORECEPTOR TYROSINE-BASED ACTIVATION MOTIF

(ITAM). B-, T- and natural killer (NK)-cell activating receptors are non-covalently associated with transmembrane proteins that contain one or more ITAMs. The structural motif (Asp/Glu-Xaa-Xaa-Tyr-Xaa-Xaa-Leu/Ile-Xaa(6–8)-Tyr-Xaa-Xaa-Leu/Ile) is tyrosine phosphorylated after ligation of the ligand-binding subunits, which triggers a cascade of intracellular events that result in cell activation.

NKT-CELL SUBSET

A heterogeneous subset of T cells the majority of which express semi-invariant T-cell receptors. In mice, NKT cells were first identified by their expression of the NK1.1 (Nkrp1c) cell-surface molecule.

γδ-TCR+ T CELLS

Unconventional T cells that express a T-cell receptor (TCR) composed of γ- and δ-subunits.

MONOMORPHIC α3 DOMAIN

The extracellular region of MHC class I molecules is composed of three domains known as α1, α2 and α3. Whereas the membrane distal α1 and α2 domains are polymorphic and form the peptide-binding groove, the membrane proximal α3 domain is well conserved among different MHC class I alleles.

HLA-E

One of the non-classical MHC class Ib molecules characterized by limited polymorphism. HLA-E preferentially assembles with a homologous set of peptides derived from the leader sequence of classical MHC class Ia molecules, but its capacity to bind and present other peptides is currently unravelling. HLA-E has also been shown to be the main ligand of CD94/NKG2A heterodimers expressed by natural killer cells and T cells.

LEUKOCYTE RECEPTOR COMPLEX

(LRC). The human LRC, localized in the q13.4 region of chromosome 19, is a cluster of genes encoding molecules that belong to the immunoglobulin family and encompasses the KIR and LIR loci.

VARIEGATION

Mechanisms that lead to different expression patterns of a particular gene cluster.

TCR-Vβ

The hypervariable region of the T-cell receptor (TCR) β-subunit. As this region is mainly implicated in the recognition of antigens, mutations that affect TCR-Vβ allow diversity of the T-cell repertoire.

MULTIGENIC AND MULTIALLELIC FAMILY

A family of molecules encoded by many different genes. For each particular locus, many different allelic forms have been described.

QA-1

This is the mouse homologue of HLA-E and so is a non-classical MHC class Ib molecule. It preferentially assembles with the Qa-1 determinant modifier (Qdm) peptide derived from the leader sequence of classical MHC class Ia molecules, but has the capacity to bind and present other peptides. Similar to HLA-E, Qa-1 is the main ligand of CD94/NKG2A heterodimers expressed by mouse natural killer cells and T cells.

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Vivier, E., Anfossi, N. Inhibitory NK-cell receptors on T cells: witness of the past, actors of the future. Nat Rev Immunol 4, 190–198 (2004). https://doi.org/10.1038/nri1306

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