Report from the Killer-cell Immunoglobulin-like Receptors (KIR) component of the 17th International HLA and Immunogenetics Workshop

Abstract

The goals of the KIR component of the 17th International HLA and Immunogenetics Workshop (IHIW) were to encourage and educate researchers to begin analyzing KIR at allelic resolution, and to survey the nature and extent of KIR allelic diversity across human populations. To represent worldwide diversity, we analyzed 1269 individuals from ten populations, focusing on the most polymorphic KIR genes, which express receptors having three immunoglobulin (Ig)-like domains (KIR3DL1/S1, KIR3DL2 and KIR3DL3). We identified 13 novel alleles of KIR3DL1/S1, 13 of KIR3DL2 and 18 of KIR3DL3. Previously identified alleles, corresponding to 33 alleles of KIR3DL1/S1, 38 of KIR3DL2, and 43 of KIR3DL3, represented over 90% of the observed allele frequencies for these genes. In total we observed 37 KIR3DL1/S1 allotypes, 40 for KIR3DL2 and 44 for KIR3DL3. As KIR allotype diversity can affect NK cell function, this demonstrates potential for high functional diversity worldwide. Allelic variation further diversifies KIR haplotypes. We determined KIR3DL3~KIR3DL1/S1~KIR3DL2 haplotypes from five of the studied populations, and observed multiple population-specific haplotypes in each. This included 234 distinct haplotypes in European Americans, 191 in Ugandans, 35 in Papuans, 95 in Egyptians and 86 in Spanish populations. For another 35 populations, encompassing 642,105 individuals we focused on KIR3DL2 and identified another 375 novel alleles, with approximately half of them observed in more than one individual. The KIR allelic level data gathered from this project represents the most comprehensive summary of global KIR allelic diversity to date, and continued analysis will improve understanding of KIR allelic polymorphism in global populations. Further, the wealth of new data gathered in the course of this workshop component highlights the value of collaborative, community-based efforts in immunogenetics research, exemplified by the IHIW.

Conservation, Extensive Heterozygosity, and Convergence of Signaling Potential All Indicate a Critical Role for KIR3DL3 in Higher Primates

“…The amino acid differences that define human KIR3DL3 variation are shown in Figure S3. In compiling all of the human KIR3DL3 variants, we fully characterized 29 novel alleles (Figure 3A) that had been identified through study of 1,000 individuals from Europe and 200 from Papua New Guinea (61). These alleles represent 19 distinct KIR3DL3 allotypes, nine synonymous variants, and one allele encoding a premature stop codon in D0 (Figure 3A).…”

“…In addition to 120 human KIR3DL3 CDS alleles obtained from the IPD, we included nine identified from southern African KhoeSan (25), and 29 identified during the 17th International HLA and Immunogenetics Workshop (IHIW) (61). The latter represent alleles identified from European ( N = 1,000) and Papua New Guinean ( N = 200) subjects, using high throughput sequencing (62).…”

“…Frequencies of KIR and HLA class I alleles were obtained from the following populations: Yucpa Amerindians (66), Maori (72), sub-Saharan Africans: Ga-Adangbe from Ghana (73), and Nama and Khomani San from southern Africa (25), Europeans and Papua New Guineans (61), and Chinese Southern Han [(97–99); Deng et al, unpublished]. Heterozygosity was calculated according to Nei and Tajima (100) using the allele frequencies within each population.…”

Key Aspects of the Immunobiology of Haploidentical Hematopoietic Cell Transplantation

“…KIRs with long tails are generally inhibitory (with exception of KIR2DL4) and KIRs with short tails function as activating receptors according to presence or absence of immunoreceptor tyrosine-based inhibitory motifs (ITIMs) (124). There is tremendous variability within the KIR repertoire owing to a high degree of polymorphism among individual KIR genes as well as their organization and recombination within haplotypes ( Figures 5B,C) (125). An individual's genetic KIR repertoire is determined by the inherited composition of centromeric and telomeric A and B haplotypes ( Figure 5B).…”

Killer‐cell immunoglobulin‐like receptor assessment algorithms in haemopoietic progenitor cell transplantation: current perspectives and future opportunities

“…The variety of defined KIR alleles is rapidly expanding, with each new study of KIR alleles likely to identify novel and previously unpublished alleles. This has led to the suggestion that the degree of polymorphism of KIR in the global population may ultimately equal or exceed that of HLA, currently accepted as the most polymorphic gene system in the human genome …”