Killer immunoglobulin-like receptors

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Killer Ig-like receptors (KIRs) are surface inhibitory receptors specific for allelic forms of human leukocyte antigen (HLA) class I molecules, which are expressed by natural killer (NK) cells and a subset of T lymphocytes. Upon engagement with HLA class I molecules, KIRs block NK cell activation and function. Cells lacking HLA class I molecules are promptly killed by NK cells because of the predominant effect of several activating NK receptors. The NK-mediated killing of these cells might represent an important defence mechanism, antagonizing spreading of pathogens and tumours. Evidence has been accumulated that KIR-encoding genes have evolved and diversified rapidly in primates and in humans. Similar to HLA loci, KIR sequences are highly polymorphic and, moreover, KIR haplotypes greatly vary in the number of the type of genes they contain. KIR gene expression is regulated by mechanisms of DNA methylation. As recently shown, the HLA class I regulated control of NK cell function can be exploited in an allogeneic bone marrow transplantation setting to eradicate acute myeloid leukaemias.

Introduction

Natural killer (NK) cells in contrast to T or B lymphocytes (i.e. the players of the adaptive immune responses) do not express clonally distributed rearranging receptors for antigen [1]. NK cells are major components of the innate immunity — a defence system that has been shadowed by the adaptive immunity, characterised by antigen-specific receptors, strength and ability to confer a durable memory. However, during recent years, the innate immunity has gained noticeable consideration because of a better appreciation of its crucial role in defences, and because of major advances in phenotypic and functional characterisation of different cell types that are part of the innate immune system, primarily of NK cells 1., 2., 3.. Thus, it became evident that the innate immunity is essential to limit or eradicate pathogens during the early phases of a primary infection — that is, before T and B cells can mount efficient responses. Indeed, NK cells and phagocytes that do not require clonal expansion can enter and defend a tissue almost as soon as it becomes infected. These effector cells can eliminate pathogens by different mechanisms, kill infected cells and secrete cytokines, which further recruit other cells of the innate immunity. Moreover, because of interaction with dendritic cells, NK cells may greatly influence the magnitude and the quality of subsequent adaptive immune responses [4]. The prompt and different reactions of the innate immunity to pathogen invasions may actually lead to termination of infection without the involvement of adaptive immunity and with no development of manifest disease [5]. Major advances in understanding different cell types of the innate immunity are owing to the discovery and the molecular characterisation of numerous surface receptors that play a crucial role in cell functions and to the identification of the genes that encode such receptors. The structure and the evolution of some of these defence genes reflect the need to adapt to mechanisms of evasion by different pathogens. A key example is represented by the human leukocyte antigen (HLA) class I specific human killer Ig-like receptors (KIRs) encoding genes [6], which are discussed in more detail in this paper.

Section snippets

Surface receptors regulating natural killer cell function

Only in recent years have we acquired a fairly accurate perception of the general mechanisms that regulate the activation and function of NK cells. Indeed, the molecular strategies that allow NK cells to spare normal cells and kill tumour or virus-infected cells have now been clarified. Thus, NK cells are regulated by an array of surface receptors with either activating or inhibitory function [7]. A prominent role is played by inhibitory receptors that specifically interact with MHC class I

Killer Ig-like receptor expression in human natural killer cells

That NK cells could sense allelic differences on haemopoietic target cells was suggested by the hybrid resistance phenomenon in which NK cells were shown to be responsible for rejection of parental bone marrow grafts in F1 hybrid mice [28]. Parallel studies in mice and in humans begun to unravel the molecular mechanisms underlying the NK-mediated function and lysis of tumour cells. In humans, two surface molecules expressed by subsets of NK cells and capable of modulating the NK cell function

Genetic basis of killer Ig-like receptor diversity

As discussed above, KIRs differ for the number of extracellular Ig-like domains and for the length of their cytoplasmic tail. From an evolutionary point of view, all the various KIRs appear to derive from a KIR composed of three domains (D0, D1 and D2 domains) with a long cytoplasmic tail, although the predominant KIRs present in humans are characterised by two Ig-like domains. There are two types of KIR2D: type 1 has domains homologous to D1 and D2, whereas type 2 has domains homologous to D0

Organisation of the killer Ig-like receptor gene complex

Genes encoding for inhibitory NK receptors in humans are clustered on two different chromosomes. The C-type lectin genes (e.g. CD94 and the NKG2 receptors) are grouped in a region of chromosome 12 (natural killer complex) whereas the Ig superfamily genes, including KIRs, are clustered in the leukocyte receptor complex (LRC) on human chromosome 19q 13.4. This region encompasses over 25 genes (Figure 1). Some genes in LRC, such as the NKp46 activating receptor gene, are orthologous in humans and

Regulation of killer Ig-like receptor expression, and maintenance of the killer Ig-like receptor repertoire

As discussed above, each NK cell expresses and maintains an individual set of KIRs and thus contributes to diversify the NK cell repertoire; however, the molecular basis for generating this clonally distributed KIR expression pattern remained elusive until recently. It is of note that although KIR genes have diversified considerably their putative regulatory regions are conserved and limited indications exist for genetically encoded regulatory mechanisms that explain the differential KIR

Comparison of killer Ig-like receptors in phylogeny

The lack of KIR genes in mice, together with the remarkable gene and allele diversity in human KIR haplotypes, suggests a recent and rapid evolution of the KIR gene family. To better clarify this concept comparison of KIR has been performed in several primate species. These studies have unequivocally demonstrated the occurrence of rapid changes in the KIR gene family over a relatively short time period (<15 million years).

The common chimpanzee (a species diverged from humans only 5–6 million

Conclusions

Identification of KIR molecules has allowed us to understand the molecular mechanism by which NK cells exert their function and eliminate cells displaying downregulation of MHC class I consequent to viral infection or tumour transformation. KIR expression on NK cells confers to these cells of the innate immunity a sophisticated mechanism to sense even single allelic losses on potential target cells because of the clonally distributed KIR expression on NK cells. KIR expression is under an

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

This work was supported by grants awarded by Associazione Italiana per la Ricerca sul Cancro (AIRC), Istituto Superiore di Sanità (ISS), Ministero della Salute (RF 2002/149), Ministero dell’Istruzione dell’Università e della Ricerca (MIUR), Ministero dell’Università e della Ricerca Scientifica e Tecnologica (MURST) and Compagnia di San Paolo. We thank Cinzia Miriello and Stefano Canu for secretarial assistance.

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