ReviewNatural killer cells and their receptors
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 10ā15% 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 ānatural 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 āBw6 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 ātricksā 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.
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