Review
Natural killer cells and their receptors

https://doi.org/10.1016/S0966-3274(02)00062-XGet rights and content

Abstract

Natural killer (NK) cells have been known for a long time to be a very important component of the innate immune system. However, it is only during the last 10 years that knowledge of their receptors has emerged. Described in the present review are those receptor families killer inhibitory receptor (KIR) (belonging to the immunoglobulin superfamily), and killer lectin like receptor (KLR) CD94/NKG2, that both use HLA as a ligand and have inhibiting and activating types of receptors, and natural cytotoxic receptors (NCR) which do not associate with HLA. Association of the receptor gives rise to either an inhibiting or activating signal leading to either failure or success in lysing a target cell. The KIR receptors are very polymorphic both in the number of genes expressed in an individual and the alleles present for a gene. They would appear to have had a rapid evolution compared to the CD94/NKG2 receptors. The roles that NK cells and their receptors have with various facets of transplantation, disease, pregnancy and control of virus infection in humans are described.

Section snippets

NK cells

Human natural killer (NK) cells are bone marrow-derived lymphocytes that share a common progenitor with T cells, do not express antigen-specific cell surface receptors and comprise 10ā€“15% of all circulating lymphocytes. Owing to their early production of cytokines and chemokines and their ability to lyse target cells without prior sensitisation (hence the term ā€˜natural killerā€™ cells), NK cells are crucial components of the innate immune system, providing a first line of defence against

Missing self hypothesis

Class I major histocompatibility complex (MHC) glycoproteins are important in controlling the effector functions of both cytotoxic T-cells and NK cells. However, unlike T-cells, which recognise antigen as peptide fragments bound to MHC molecules, NK cells become functional in the absence of class I MHC proteins on target cells. This missing-self hypothesis proposes that T-cell and NK-cell immunity represent complementary arms of the cellular immune response: T-cells recognise and are activated

NK cell receptors

There are two families of NK cell receptors, the Immunoglobulin Superfamily and the C-type lectin. Numerous members of the Immunoglobulin Superfamily such as human killer cell Ig-like receptor (KIR), leucocyte immunoglobulin-like receptor (LILR), [previously known as either immunoglobulin like transcript (ILT) or leucocyte inhibitory receptor (LIR), leucocyte-associated inhibitory receptor (LAIR), FcĪ±R and the activating NK receptor NKp46 are clustered in the leucocyte receptor complex (LRC)

KIR

KIRs are named according to whether they have two domains (2D) or three domains (3D) (D0, D1, D2) and to whether they possess a short (S) or long (L) cytoplasmic tail (Table 1). Those with long cytoplasmic tails contain immunoreceptor tyrosine-based inhibitory motifs (ITIM) and have an inhibitory function, although the function of 2DL4 has been questioned while those with short cytoplasmic tails have a potentially activating function (see Section 7). Despite being inhibitory or activating, KIR

CD94/NKG2 receptors

The CD94/NKG2 receptors are disulfide-linked heterodimers, composed of an invariant common sub-unit, CD94 [39], that is linked to a distinct glycoprotein encoded by a gene of the NKG2 family [40], [41], [42]. Whereas CD94 is a single gene with limited or no allelic polymorphism, the NKG2 family comprises five genes designated NKG2A, NKG2C, NKG2D, NKG2E and NKG2F (Fig. 4) [43], [44], [45], [46]. NKG2B is an alternative splice variant of NKG2A. Recently new nomenclature has been given to these

Natural cytotoxic receptors (NCR)

The existence of NK cell receptors specific for non-HLA ligands has been suspected for many years, since it is well established that NK cells kill HLA class I negative cells [27], [57]. Recently such receptors have been found. Three of them, NKp46 and NKp30, expressed on resting and activated NK cells, and NKp44 on activated cells only, belong to the Immunoglobulin Superfamily and have been called natural cytotoxicity receptors (NCR) [58]. (NKG2D is also considered as a NCR see Section 5.)

Inhibition and activation signalling

KIR with long cytoplasmic tails contain two immunoreceptor tyrosine-based inhibitory motifs (ITIM) which are responsible for the inhibitory function of these molecules. Engagement of receptor with its class I ligand leads to phosphorylation of the tyrosine residues within the ITIM (Fig. 5). The ITIM then recruits and activates the tyrosine phosphatase (SHP-1) which prevents the phosphorylation events associated with cellular activation, leading to the inhibition of NK-cell mediated cytotoxicity

Evolution of receptors

There is a very high level of homology in both coding and non-coding sequences within the KIR genes consistent with their recent evolution. This is supported by the facts that almost all of the KIR-associated Alu sequences are of the evolutionarily more recent S subclass [71] and although no orthologues of the KIR have been found in the rodent, KIR receptors have been found in the chimpanzee [72]. The rodent does, however, possess CD94-NKG2 genes and it would appear that CD94/NKG are more

Why have so many receptor types?

Whereas KIRs would be beneficial to detect the loss of one class I ligand, CD94/NKG2A/C/E receptors would be useful for loss of several or all class I, perhaps when a virus disrupts MHC class I synthesis. There also could be a difference in the sensitivity of each group of receptors to alteration in the expression of class I antigens. It would appear NK cells have failed to develop inhibitory receptors of the KIR family for many HLA-A and ā€“Bw6 associated antigens. Thus CD94/NKG2A/C/E would be

Bone marrow transplantation

For many years it had been known that the offspring of two different inbred strains of mice would accept organ grafts from either parent but would reject bone marrow grafts [89]. This was termed hybrid resistance but no explanation was forthcoming until knowledge of NK cell inhibiting receptors and their class I ligands became available. Some NK cells in the offspring will be inhibited by class I antigens from one parent, while other NK cells will be inhibited by class I antigens of the other

Solid organ transplantation

NK cell infiltration of renal and cardiac allografts occurs shortly after transplantation and usually before T cell infiltration. Although activation is evident the ability of NK cells to directly mediate rejection of the grafts is unlikely, but may influence the rejection process [97].

In terms of xenotransplantation the susceptibility of porcine endothelial cells (PEC) to human NK cytotoxicity may be due to an incompatibility between porcine class I antigens and human NK cell receptors.

Disease

There are frequent associations between infections and autoimmune disease in humans [99]. NK cells could be involved in autoimmunity. They are capable of releasing cytokines (involved in differentiation of naı̈ve T cells into Th1 and Th2 phenotypes) and their activity is prevented by inhibitory receptors, impairment of which could lead to activation. NK cells are frequently present in many of the organs targeted in autoimmune disease ā€” muscle, rheumatoid synovial tissue, pancreas, brain,

Pregnancy

Specialised cells of the NK lineage (uterine NK cells) comprise the major population of lymphocytes accumulating at the maternal-foetal interface during pregnancy [108]. Although the role of these NK cells in pregnancy is not known, experimental findings have shown that mice deficient in uterine NK cells will have a failed pregnancy [109].

The placental trophoblast which forms the interface between foetal and maternal tissues express HLA-Cw, -E and -G but not HLA-A or -B [110] although HLA-Cw is

Virus

The ability of certain viruses to down regulate HLA class I expression provides a clever strategy to evade host T cell immunity [112]. However, this would leave the virus open to attack by NK cells. A number of viruses have, however, further ā€˜tricksā€™ in their armoury to deal with the NK response. NK cells can specifically recognise an open reading frame in human cytomegalovirus (HCMV) that encodes a HLA class I-like heavy chain. This viral class I homologue (UL18) can inhibit NK cell activity

NKT lymphocytes

NK receptors have also been found expressed on subsets of activated T cells of memory phenotype, mostly CD8+, in which they can inhibit TCR mediated functions [121]. The T cells could be of either TCRĪ±Ī² or TCRĪ³Ī“ phenotype but in an individual they express a limited number of TCRVĪ²s [122], [123], [124]. A striking characteristic of NKT cells is their ability to produce high levels of IL-4, IFN-Ī³ and other cytokines within a few hours of in vivo activation [125].

Roles for NKT cells have been

Future

It will be imperative to define the variability at the gene level and the extent of allele polymorphism for each gene. The significance of this polymorphism and its interaction with the function of the KIR remains to be determined. Thereafter it is predicted, similar to what happened in the HLA field, that there will be a explosion of interest in examining this polymorphism in many diseases, especially cancer and those diseases caused by viruses. There will also be great interest in the

Acknowledgements

We thank A.M. McCann for her patience and skill in typing this manuscript. We are also indebted to M. Carrington, P. Norman and P. Parham for supplying unpublished data.

References (128)

  • L.L. Lanier et al.

    Association of DAP12 with activating CD94/NKG2C NK cell receptors

    Immunity

    (1998)
  • S.I. Khakoo et al.

    Rapid evolution of NK cell receptor systems demonstrated by comparison of chimpanzees and humans

    Immunity

    (2000)
  • J. Trowsdale

    Genetic and functional relationships between MHC and NK receptor genes

    Immunity

    (2001)
  • N.M. Valiante et al.

    Functionally and structurally distinct NK cell receptor repertoires in the peripheral blood of two human donors

    Immunity

    (1997)
  • L. Meyaard et al.

    LAIR-1, a novel inhibitory receptor expressed on human mononuclear leukocytes

    Immunity

    (1997)
  • G. Nicoll et al.

    Identification and characterization of a novel Siglec, Siglec-7, expressed by human natural killer cells and monocytes

    J Biol Chem

    (1999)
  • M. Bennett et al.

    Hybrid resistance: ā€˜Negativeā€™ and ā€˜positiveā€™ signalling of murine natural killer cells

    Semin Immunol

    (1995)
  • J.O. Manilay et al.

    Natural killer cells and their role in graft rejection

    Curr Opin Immunol

    (1998)
  • I. Scott et al.

    Molecular typing shows a high level of HLA class I incompatibility in serologically well matched donor/patient pairs: implications for unrelated bone marrow donor selection

    Blood

    (1998)
  • V.K. Prasad et al.

    HLA-C disparity between patients and unrelated donors matched for HLA-A, -B and -RB1 alleles: impact of serological vs. DNA typing for HLA-A and -B loci

    Biol Blood Marrow Transplant

    (1999)
  • L. Ruggeri et al.

    Role of natural killer cell alloreactivity in HLA-mismatched hematopoietic stem cell transplantation

    Blood

    (1999)
  • W.M. Baldwin et al.

    Innate immune responses to transplants: a significant variable with cadaver donors

    Immunity

    (2001)
  • W.E. Seaman

    Natural killer cells and natural killer T cells

    Arthr Rheum

    (2000)
  • K. Ogata et al.

    Association between natural killer cell activity and infection in immunologically normal elderly people

    Clin Exp Immunol

    (2001)
  • R. Biassoni et al.

    Role of amino acid position 70 in the binding affinity of p50.1 and p58.1 receptors for HLA-Cw4 molecules

    Eur J Immunol

    (1997)
  • M. Vales-Gomez et al.

    Differential binding to HLA-C of p50-activating and p58-inhibitory natural killer cell receptors

    Proc Natl Acad Sci USA

    (1998)
  • I.H. Westgaard et al.

    Identification of a human member of the Ly-49 multigene family

    Eur J Immunol

    (1998)
  • R. Biassoni et al.

    The human leukocyte antigen (HLA)-C specific ā€˜activatoryā€™ or ā€˜inhibitoryā€™ natural killer cell receptors display highly homologous extracellular domains but differ in their transmembrane and intracytoplasmic portions

    J Exp Med

    (1996)
  • A. Selvakumar et al.

    Genomic organization and allelic polymorphism of the human killer cell inhibitory receptor gene KIR103

    Tissue Antigens

    (1997)
  • C. Vilches et al.

    Genes encoding human killer-cell Ig-like receptors with D1 and D2 extracellular domains all contain untranslated pseudoexons encoding a third Ig-like domain

    Immunogenetics

    (2000)
  • M. Colonna et al.

    HLA-C is the inhibitory ligand that determines dominant resistance to lysis by NK1- and NK2-specific natural killer cells

    Proc Natl Acad Sci USA

    (1993)
  • A. Moretta et al.

    P58 molecules as putative receptors for major histocomaptibility complex (MHC) class I molecules in human natural killer (NK) cells. Anti-p58 antibodies reconstitute lysis of MHC class I-protected cells in NK clones displaying different specificities

    J Exp Med

    (1993)
  • R. Biassoni et al.

    Amino acid substitutions can influence the natural killer (NK)-mediated recognition of HLA-C molecules. Role of serine-77 and lysine-80 in the target cell protection from lysis mediated by ā€˜group 2ā€™ or ā€˜group 1ā€™ NK clones

    J Exp Med

    (1995)
  • A. Selvakumar et al.

    NK cell receptor gene of the KIR family with two Ig domains but highest homology to KIR receptors with three Ig domains

    Tissue Antigens

    (1996)
  • A. Rajagopalan et al.

    A human histocompatibility leukocyte antigen (HLA)-G-specific receptor expressed on all natural killer cells

    J Exp Med

    (1999)
  • V. Litwin et al.

    NKB1: a natural killer cell receptor involved in the recognition of polymorphic HLA-B molecules

    J Exp Med

    (1994)
  • C. Dohring et al.

    A human killer inhibitory receptor specific for HLA-A

    J Immunol

    (1996)
  • D. Pende et al.

    The natural killer cell receptor specific for HLA-A allotypes: a novel member of the p58/p70 family of inhibitory receptors that is characterised by 3 immunoglobulin domains and is expressed as a 140 kDa disulphide linked dimer

    J Exp Med

    (1996)
  • C. Vilches et al.

    KIR2DL5, a novel killer-cell receptor with a D0 D2 configuration of immunoglobulin like domains

    J Immunol

    (2000)
  • N. Gomez-Lozano et al.

    Killer-cell immunglobulin-like receptor gene haplotypes contain between zero and two KIR2DL5 loci

    Eur J Immunogenet

    (2001)
  • J.C. Boyington et al.

    Crystal structure of an NK cell immunoglobulin-like receptor in complex with its class I MHC ligand

    Nature

    (2000)
  • M.S. Malnati et al.

    Peptide specificity in the recognition of MHC class I by natural killer cell clones

    Science

    (1995)
  • M. Peruzzi et al.

    Peptide sequence requirements for the recognition of HLA-B*2705 by specific natural killer cells

    J Immunol

    (1996)
  • S. Rajagopalan et al.

    The direct binding of a p58 killer cell inhibitory receptor to human histocompatibility leukocyte antigen (HLA)-Cw4 exhibits peptide selectivity

    J Exp Med

    (1997)
  • L.L. Lanier

    NK cell receptors

    Annu Rev Immunol

    (1998)
  • C.C. Winter et al.

    A single amino acid in the p58 killer cell inhibitory receptor controls the ability of natural killer cells to discriminate between the two groups of HLA-C allotypes

    J Immunol

    (1997)
  • K.A. Crum et al.

    Development of a PCR-SSOP approach capable of defining the natural killer cell inhibitory receptor (KIR) gene sequence repertoires

    Tissue Antigens

    (2000)
  • F. Williams et al.

    Allele resolution of HLA-A using oligonucleotide probes in a two stage typing strategy

    Tissue Antigens

    (1999)
  • C.S. Witt et al.

    Population frequencies and putative haplotypes of the killer cell immunoglobulin-like receptor sequences and evidence for recombination

    Transplantation

    (1999)
  • M.P. Martin et al.

    Determination of KIR haplotypes in CEPH

    Human Immunol

    (2000)
  • Cited by (0)

    View full text