KIR2DL5: An Orphan Inhibitory Receptor Displaying Complex Patterns of Polymorphism and Expression

Abstract

A recently developed anti-KIR2DL5 (CD158f) antibody has demonstrated KIR2DL5 expression on the surface of NK and T lymphocytes, making it the last functional KIR identified in the human genome. KIR2DL5 belongs to an ancestral lineage of KIR with Ig-like domains of the D0-D2 type, of which KIR2DL4, an HLA-G receptor, is the only other human member. Despite KIR2DL4 and KIR2DL5 being encoded by genes with similar domain usage, several KIR2DL5 functions resemble more closely those of KIR recognizing classical HLA class I molecules – surface-expressed KIR2DL5 inhibits NK cells through the SHP-2 phosphatase and displays a clonal distribution on NK and T lymphocytes. No activating homolog of KIR2DL5 has been described in any species. The genetics of KIR2DL5 is complicated by duplication of its gene in an ancestor of modern humans living ∼1.7 million years ago. Both KIR2DL5 paralogs have undergone allelic diversification; the centromeric gene is most often represented by alleles whose expression is silenced epigenetically through DNA methylation, thus providing a natural system to investigate the regulation of KIR transcription. The role of KIR2DL5 in immunity is not completely understood, in spite of different attempts to define its ligand. Here we revisit the most relevant characteristics of KIR2DL5, an NK-cell receptor possessing a unique combination of genetic, structural, and functional features.

Allelic Polymorphism Determines Surface Expression or Intracellular Retention of the Human NK Cell Receptor KIR2DL5A (CD158f)

“…In this study, we have addressed another source of apparent discrepancy between KIR2DL5 phenotyping and basic genotyping—lack of a detectable product despite presence of a KIR2DL5 allele with an intact RUNX site. We have shown here that this situation is regularly seen in KIR2DL5A * 005 , part of the common telomeric KIR motif 3DS1-2DL5A * 005-2DS3 * 002-2DS1-3DL2 (7, 10, 11, 17). According to our results, such phenotype can be anticipated also for KIR2DL5B * 0020106 and * 00202 , centromeric alleles governed by predictably functional promoters and encoding mature polypeptides identical to KIR2DL5A * 005 (16).…”

“…KIR2DL5 has a complex genetics due to copy number variation and allelic polymorphism (7). It is encoded in the human genome by two closely related genes— KIR2DL5A in the telomeric segment of KIR haplotypes and KIR2DL5B in the centromeric interval (8, 9).…”

“…Allelic polymorphism affects the coding and the non-coding regions of KIR2DL5 (7, 13). Of particular functional relevance is one polymorphic G > A substitution at nucleotide 97 before the initiation codon that destroys a RUNX-binding site conserved in the proximal promoter of most KIR .…”

“…Asparagine and glycine are seen in the common 2DL5A * 001 allele, in 2DL5B * 006 , and in other less-common alleles of both loci, besides being conserved in virtually all KIR, while 2DL5A * 005 on the telomeric side, the dominant centromeric allele 2DL5B * 002 and others encode aspartate and serine at those positions (7). No KIR2DL5 allele with a mixed motif has been described.…”

KIR2DL5B genotype predicts outcomes in CML patients treated with response-directed sequential imatinib/nilotinib strategy

“…Our findings suggest that even with the potent second-generation TKI nilotinib, KIR genotypes, a predetermined genetic host factor, may still be one of the most discriminatory prognostic markers available at baseline. Although the biological mechanism that underpins this observed association remains to be elucidated, KIR2DL5B encodes an inhibitory "orphan" KIR receptor (its ligand is unknown), 18 but its absence may increase efficiency of NKmediated killing of leukemic stem cells. The importance of immune responses in CML disease control with TKI therapy is consistent with effects seen with allogeneic stem cell transplant, donor lymphocyte infusions, and interferon-alfa treatment, in which the therapeutic effect is wholly or partially secondary to T-and NK-cell activity.…”