High-resolution human KIR genotyping

Abstract

Killer immunoglobulin-like receptors (KIR) regulate the function of natural killer cells through interactions with various ligands on the surface of cells, thereby determining whether natural killer (NK) cells are to be activated or inhibited from killing the cell being interrogated. The genes encoding these proteins display extensive variation through variable gene content, copy number and allele polymorphism. The combination of KIR genes and their ligands is implicated in various clinical settings including haematopoietic stem cell and solid organ transplant and infectious disease progression. The determination of KIR genes has been used as a factor in the selection of optimal stem cell donors with haplotype variations in recipient and donor giving differential clinical outcomes. Methods to determine KIR genes have primarily involved ascertaining the presence or absence of genes in an individual. With the more recent introduction of massively parallel clonal next-generation sequencing and single molecule very long read length third-generation sequencing, high-resolution determination of KIR alleles has become feasible. Determining the extent and functional impact of allele variation has the potential to lead to further optimisation of clinical outcomes as well as a deeper understanding of the functional properties of the receptors and their interactions with ligands. This review summarizes recently published high-resolution KIR genotyping methods and considers the various advantages and disadvantages of the approaches taken. In addition the application of allele level genotyping in the setting of transplantation and infectious disease control is discussed.

Adoptive cellular immunotherapy for solid neoplasms beyond CAR-T

“…KIR2DL4 resides in endosomes, and its ligand is HLA-G. Soluble HLA-G accumulates in KIR2DL4 endosomes, and its activation initiates proinflammatory and proangiogenic responses through a novel endosomal signaling pathway involving serine/threonine kinases DNA-PKcs and Akt [ 118 ]. Seventeen KIR genes (including two pseudogenes) have been discovered in the leukocyte receptor complex encoded by an approximately 150-kb segment on chromosome 19q13.14 [ 119 ].…”

Donor–Recipient Non-HLA Variants, Mismatches and Renal Allograft Outcomes: Evolving Paradigms

“…This is demonstrated by genes that show marked interindividual CNVs, such as the Killer cell immunoglobulin-like receptors genes (KIRs). Duplication of gene sequences could lead to excessive or defective production of certain peptide sequences, contributing to peptide variation and serving to induce alloimmunity (40). Recent work has also reported a role for CNV-tagging SNPs in renal allograft rejection (22).…”

HLA-B*57:01 Complexed to a CD8 T-Cell Epitope from the HSV-2 ICP22 Protein Binds NK and T Cells through KIR3DL1

“…There are at least 17 known functional members of the polymorphic KIR family. These can be activating (S type, for short cytoplasmic tail, containing an immunoreceptor-tyrosine activating motif (ITAM)) or inhibitory (L type, long cytoplasmic tail, containing an inhibitory ITIM motif) [ 9 ]. KIR are expressed by both NK cells and a subset of T cells.…”

“…Along with other HLA allelic variants sharing the Bw4 determinant, HLA-B*57:01 appears to have specificity for KIR3DL1. Most persons possess one or two functional copies of either KIR3DL1 , [ 9 , 10 , 11 ] or KIR3DS1 , an activating variant of KIR3DL1 that can occur at the same location in the KIR locus on human chromosome 19 [ 12 ]. KIR3DL1 has many allelic variants that encode different protein sequences with differing expression levels on the cell surface, which impacts the strength of NK cell inhibition [ 9 , 13 ].…”

“…Most persons possess one or two functional copies of either KIR3DL1 , [ 9 , 10 , 11 ] or KIR3DS1 , an activating variant of KIR3DL1 that can occur at the same location in the KIR locus on human chromosome 19 [ 12 ]. KIR3DL1 has many allelic variants that encode different protein sequences with differing expression levels on the cell surface, which impacts the strength of NK cell inhibition [ 9 , 13 ]. The specificity of the interaction with HLA-B*57:01 may depend on the amino acid residue 166 of KIR3DL1 (which is a leucine in the common allele KIR3DL1*001 ) [ 14 , 15 ] and can be blocked with the KIR3DL1-specific monoclonal antibody (mAb) DX9.…”