The silent KIR3DP1 gene (CD158c) is transcribed and might encode a secreted receptor in a minority of humans, in whom the KIR3DP1, KIR2DL4 and KIR3DL1/KIR3DS1 genes are duplicated

Abstract

Killer-cell Ig-like receptors (KIR) are structurally and functionally diverse, and enable human NK cells to survey the expression of individual HLA class I molecules, often altered in infections and tumors. Multiple events of non-reciprocal recombination have contributed to the rapid diversification of KIR. We show that *4.5% of the individuals of a Caucasoid population bear a recombinant allele of KIR3DP1, officially designed KIR3DP1*004, that associates tightly with gene duplications of KIR3DP1, KIR2DL4 and KIR3DL1/KIR3DS1. The KIR3DP1 gene is normally silent, but the recombinant allele carries a novel promoter sequence and, as a consequence, is transcribed in all tested individuals. Messenger RNA of KIR3DP1*004 is made up of six exons; of these, exons 1-5 are similar to, and spliced like, those encoding the leader peptide and Ig-domains of KIR3D. By contrast, exon 6 is homologous to no other human KIR sequence, but only to possible homologs in chimpanzees and rhesus macaques, and encodes a short hydrophilic tail. The putative KIR3DP1*004 product, like those of the related genes LAIR-2 and LILRA3/ILT6/LIR4, is predicted to be secreted to the extracellular medium rather than anchored to the cell membrane.

Molecular characterisation of KIR2DS2*005, a fusion gene associated with a shortened KIR haplotype

“…7 Besides point mutation, species acquire new KIR with novel functions more rapidly by asymmetric recombination. This leads, in first place, to haplotypes with gene loss and gene duplication, 14,15 which seem the origin of KIR2DS2 and KIR2DL2, encoded by paralogous genes. When recombination takes place within a gene, the resulting hybrids combine features (binding, signalling and mRNA expression) of the receptors that participated in the recombination.…”

“…We have proposed previously that such mechanism explains haplotypes carrying duplications or deletions of the same central genes in the KIR cluster-KIR3DP1, KIR2DL4 and KIR3DL1/S1. 15 The counterpart of the KIR2DS2*005-associated haplotype would be the one carrying a chimera coding for the Ig-like domains of KIR2DS3 fused to a KIR2DS2 tail, and duplicated KIR2DL2, KIR2DL5B and KIR2DS3 genes. Such haplotypes are yet to be found, and we have failed to identify the putative chimerical KIR2DS3 allele using PCR primers for its predicted sixth intron.…”

The KIR gene family: life in the fast lane of evolution

“…Comparison with the non-reciprocal recombination event involving the same two haplotypes (this issue; [22]) (Fig. 2B) suggests that there is in fact no principal distinction between the molecular events leading to reciprocal or non-reciprocal recombination in the KIR locus.…”

“…Thus, allelic variation would enable two individuals whose NK cells express KIR with similar specificity to mount quantitatively different immune responses and in this way to broaden the spectrum of resistance to infection in the population. It should of course be mentioned that alleles that confer loss of function (gene expression is completely shut down or the protein structure becomes otherwise compromised) [19][20][21] or gain of function (this issue [22]) ultimately mimic absence or presence of the respective gene and thus can change NK cell specificity, too.…”

“…At the putative recombination breakpoint, a novel hybrid gene was generated by linking the promoter from KIR2DL5A to the coding region of the silent pseudogene KIR3DP1. In this issue of the European Journal of Immunology, Gómez-Lozano et al show that the resulting new allele, named KIR3DP1*004, is in fact transcribed and might be properly expressed in NK cells as a soluble KIR [22]. Although the resulting two novel haplotypes are very dissimilar in gene content, they apparently both remain represented in the population [25,33].…”