The remaining haplotypes collectively comprise the KIR B-haplotypes, exhibiting differing numbers and types of activating KIR in the centromeric or telomeric portions 4, 5, 6. Some patterns of genetic combination are well-recognized and have led to the designation of the canonical KIR haplotype-A, characterized by gene content as presence of the centromeric KIR2D元 and KIR2DL1 and the telomeric KIR3DL1, in the absence of all activating KIR, with the exception of the telomeric KIR2DS4. Significant diversity exists from individual to individual both at the KIR gene content and allele level. Additional inhibitory KIR molecules include KIR3DL1, which recognizes the Bw4 epitope exhibited by some HLA-A and HLA-B allotypes, and KIR3DL2, which recognizes the HLA-A3, HLA-A11, and HLA-B27 proteins 2, 3. Between the KIR2DL receptors and their specificities, nearly all HLA-C allotypes have a cognate inhibitory KIR. The KIR2DL receptors exclusively recognize HLA-C molecules: KIR2DL1 recognizes HLA-C allotypes characterized by Lys80 (collectively referred to as HLA-C group 2) KIR2D元 recognizes predominantly HLA-C allotypes characterized by Asn80 (HLA-C group 1) while KIR2DL2 recognizes members of both HLA-C groups 1 and 2 2. In humans, the principal receptors mediating education are the polygenic, polymorphic inhibitory killer cell immunoglobulin-like receptors (KIR), which recognize antigens presented by HLA-A, -B, and –C molecules 2. This process, termed “education” or “licensing” is enabled through interactions between inhibitory receptors on NK cells with “self” MHC, that permit cytotoxic granule release for target cell killing, but also inhibition of the NK cell upon binding to cognate MHC. In summary, our findings enable rapid typing of the most common KIR2DL receptor subtypes, allowing more accurate prediction of co-inheritance and providing a useful tool for the discrimination of observed differences in surface expression and effector function among NK cells exhibiting disparate KIR2DL allotypes.Īs key members of the innate immune response, natural killer (NK) cells survey surrounding cells, discriminating damaged or infected cells from healthy cells, in part via receptor recognition of altered self-MHC on damaged cells 1.
Linkage disequilibrium analysis between the different KIR2DL alleles revealed that seven allelic combinations represent more than 95% of the observed population genotypes for KIR2DL1/L2/元. Using KIR allele data from a cohort of 426 European-Americans, we identified the most common KIR2DL subtypes and developed the high-throughput PCR-based methodology, which was validated on a separate cohort of 260 healthy donors. Six reactions define six subgroups of KIR2DL1 four reactions define three subgroups of KIR2DL2 and five reactions define four subgroups of KIR2D元. Use of the ARMS design makes the method reliable and usable as a kit, with all reactions utilizing the same conditions.
We have developed a global intermediate resolution amplification-refractory mutation system (ARMS) PCR-SSP method for distinguishing functionally relevant subgroups of the KIR2DL receptors, as defined by phylogenetic study of the protein sequences. Allelic diversity of the KIR2DL receptors drive differential expression and ligand-binding affinities that impact natural killer cell function and patient outcomes for diverse cancers.
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