Korean J Hematol.  2011 Dec;46(4):216-228. 10.5045/kjh.2011.46.4.216.

Human diversity of killer cell immunoglobulin-like receptors and disease

• Rajalingam R

• KMID: 2251982
• DOI: http://doi.org/10.5045/kjh.2011.46.4.216

Abstract

Natural Killer (NK) cells are the third population of lymphocyte in the mononuclear cell compartment that triggers first-line of defense against viral infection and tumor transformation. Historically, NK cells were thought of as components of innate immunity based on their intrinsic ability to spontaneously kill target cells independent of HLA antigen restriction. However, it is now clear that NK cells are quite sophisticated and use a highly specific and complex target cell recognition receptor system arbitrated via a multitude of inhibitory and activating receptors. Killer cell immunoglobulin-like receptors (KIR) are the key receptors of human NK cells development and function. To date, fourteen distinct KIRs have been identified: eight are inhibitory types, and six are activating types. The number and type of KIR genes present varies substantially between individuals. Inhibitory KIRs recognize distinct motifs of polymorphic HLA class I molecules. Upon engagement of their specific HLA class I ligands, inhibitory KIR dampen NK cell reactivity. In contrast, activating KIRs are believed to stimulate NK cell reactivity when they sense their ligands (unknown). KIR and HLA gene families map to different human chromosomes (19 and 6, respectively), and their independent segregation produces a wide diversity in the number and type of inherited KIR-HLA combinations, likely contributing to overall immune competency. Consistent with this hypothesis, certain combinations of KIR-HLA variants have been correlated with susceptibility to diseases as diverse as autoimmunity, viral infections, and cancer. This review summarizes our emerging understanding of KIR-HLA diversity in human health and disease.

Keyword

NK cells; Innate immunity; HLA; KIR; Polymorphism; Immune genes

MeSH Terms

Autoimmunity
Chromosomes, Human
Humans
Immunity, Innate
Killer Cells, Natural
Ligands
Lymphocytes
Receptors, KIR
Ligands
Receptors, KIR

Figure

• 

  Fig. 1 Professional killer cell response. Natural killer (NK) cells and cytotoxic T cells (CTL) are professional killer cells and share several common features but differ by their HLA class I-specific receptors that are used to distinguish unhealthy targets from the healthy host cells. CTLs express activating T cell receptors (TCR) while NK cells express both inhibitory and activating receptors. No activation is triggered if the TCR recognize a self-peptide laden HLA class I molecule (a). TCR can trigger cytolysis if it detects a viral peptide loaded in the groove of HLA class I molecules of infected cells (b). Contrarily, the inhibitory receptors of NK cell recognize HLA class I molecules and trigger signals that stop spontaneous lytic activity of NK cells (c). By expressing normal levels of HLA class I molecules, the healthy cells are tolerant to NK cell lysis. Downregulation of HLA class I expression due to tumor transformation or viral infection relieves the inhibitory influence on NK cells, permitting NK cells to lyse the unhealthy target cells (d). The NK cell lysis can be augmented by further interactions between the activating receptors and putative ligands expressed upon infection or transformation (e).

• 

  Fig. 2 Killer cell Immunoglobulin-like Receptors (KIR). Fourteen distinct KIR receptors have been characterized in humans that comprise either two (2D) or three (3D) extracellular immunoglobulin-like domains and either a long (L) or short (S) cytoplasmic tail. Six KIR receptors are activating types and the remaining KIR are inhibitory types. The ITIM motifs in the cytoplasmic tails of inhibitory KIRs are shown as blue boxes, and positively charged residues in the transmembrane regions of activating KIRs are shown as yellow circles. The inhibitory KIR receptors bind to distinct HLA class I allotypes and the ligands for most activating KIR receptors are unknown. The number of protein sequence variants characterized to date for each KIR receptor is provided. This data was extracted from the IPD-KIR database (http://www.ebi.ac.uk/ipd/kir/stats.html; Release 2.4.0; April 2011) that provides a centralized repository for human KIR sequences.

• 

  Fig. 3 KIR haplotypes differ by gene content. Map of KIR haplotypes as determined by sequencing genomic clones and haplotype segregation analysis in families. Haplotype 1 represents group-A KIR haplotype and the remainder group-B haplotypes (haplotypes 2-22). The framework genes, present in all haplotypes are shown in dark boxes; genes encoding activating KIR are in orange boxes; and those for inhibitory receptors are in blue boxes. The KIR2DP1 and 3DP1 are pseudogenes that do not express a receptor. Maps are not drawn to scale.

• 

  Fig. 4 Centromeric and telomeric halves of KIR haplotypes. A stretch of 14 kb DNA with numerous L1 repeats that interconnects KIR3DP1 and KIR2DL4 divides the KIR haplotype into two halves. The centromeric half is delimited by 3DL3 and 3DP1, while the telomeric half is delimited by 2DL4 and 3DL2. Multiple reciprocal meiotic recombination events between 3DP1 and 2DL4 shuffle the centromeric (c) and telomeric (t) motifs, and thus diversify gene content of KIR haplotypes across individuals and populations. Most of the KIR gene content haplotypes published to date can be explained by the recombination of these 10 centromeric and 10 telomeric gene content motifs. The framework genes, present in all haplotypes are shown in dark boxes; genes encoding activating KIR are in orange boxes; and those for inhibitory receptors are in blue boxes. The KIR2DP1 and 3DP1 are pseudogenes that do not express a receptor. Letter 'A' in gene-content motif identification indicates parts of group-A haplotypes, while 'B' indicates parts of group-B haplotypes.

• 

  Fig. 5 KIR and HLA gene families are unlinked and located on different human chromosomes, 19 and 6 respectively. Both gene families evolve rapidly and feature substantial variation between haplotypes in the number and type of genes. Panel I illustrates variation between parents in KIR and HLA haplotypes. Panel II illustrates all four possible types of gametes from each parent assorted with different combination of one KIR haplotype and one HLA haplotype. Random associations of gametes form zygotes of the next generation carrying one of the 16 possible combinations of paternal and maternal KIR and HLA haplotypes, producing substantial diversity between offspring in the number and type of inhibitory KIR-HLA combinations and activating KIR genes inherited (Panel III).

• 

  Fig. 6 A and B haplotype distribution varies across distinct populations. The A and B KIR haplotypes are approximately equally distributed in Caucasians and Africans. In contrast, the prevalence of A haplotypes dominates over the B haplotypes in Northeast Asians (Chinese, Japanese, and Koreans) and vice versa in the natives of America, Australia, and India. As we described elsewhere, the frequency of group A and B KIR haplotypes were predicted from the KIR gene content data published previously for other populations [112].

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