A common KIR2DS4 deletion variant in the human that predicts a soluble KIR molecule analogous to the KIR1D molecule observed in the rhesus monkey

Maxwell, Lynn D; Wallace, Andrew; Middleton, Derek; Curran,

doi:10.1034/j.1399-0039.2002.600307.x

Cited by 128 publications

(108 citation statements)

References 21 publications

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“…Likewise, it was not possible to analyze the effect of the KIR2DS4 gene (located in the A-haplotype telomeric segment) because of a deletion variant allele that encodes for a nonfunctional receptor in as much as ;80% of individuals. 32 In an attempt to define the underlying mechanism in vitro, we found that KIR2DS1 triggered NK cells to release IFN-g upon interaction with KIR-ligand-mismatched, HLA-C2/C2 LPS-, or A fumigatuspulsed DCs and that IFN-g release was inhibited when KIR2DS1-HLA-C2 interaction was blocked. One may speculate that enhanced IFN-g production played a role in improving responsiveness to pathogens.…”

Section: Discussionmentioning

confidence: 99%

“…a KIR2DS4 deletion variant allele encodes for a nonfunctional receptor in as much as ;80% of individuals). 32 The others are either heterozygous or homozygous for group B KIR haplotypes that carry not only inhibitory KIR genes but also various combinations of activating KIR genes (KIR2DS1, 2, 3, 5, and 3DS1). Little is known about their ligands except that KIR2DS1 binds HLA-C group 2 molecules.…”

Section: Introductionmentioning

confidence: 99%

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Haploidentical hematopoietic transplantation from KIR ligand–mismatched donors with activating KIRs reduces nonrelapse mortality

Mancusi¹,

Ruggeri²,

Urbani³

et al. 2015

Blood

103

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Key Points• Haploidentical transplantation from KIR ligand-mismatched donors with activating KIRs reduces nonrelapse mortality and improves survival.• Activating KIR genetics should be considered when selecting donors for T cell-depleted haploidentical hematopoietic transplantation.Because activating killer cell immunoglobulinlike receptors (KIRs) are heterogeneously expressed in the population, we investigated the role of donor activating KIRs in haploidentical hematopoietic transplants for acute leukemia. Transplants were grouped according to presence vs absence of KIR-ligand mismatches in the graft-vs-host direction (ie, of donorvs-recipient natural killer [NK]-cell alloreactivity). In the absence of donor-vs-recipient NK-cell alloreactivity, donor activating KIRs had no effects on outcomes. In the 69 transplant pairs with donor-vs-recipient NK-cell alloreactivity, transplantation from donors with KIR2DS1 and/or KIR3DS1 was associated with reduced risk of nonrelapse mortality, largely infection related (KIR2DS1 present vs absent: hazard ratio [HR], 0.25; P 5 .01; KIR3DS1 present vs absent: HR, 0.18; P 5 .006), and better event-free survival (KIR2DS1 present vs absent: HR, 0.31; P 5 .011; KIR3DS1 present vs absent: HR, 0.30; P 5 .008). Transplantation from donors with KIR2DS1 and/or KIR3DS1 was also associated with a 50% reduction in infection rate (P 5 .003). In vitro analyses showed that KIR2DS1 binding to its HLA-C2 ligand upregulated inflammatory cytokine production by alloreactive NK cells in response to infectious challenges. Because ∼40% of donors able to exert donor-vs-recipient NK-cell alloreactivity carry KIR2DS1 and/or KIR3DS1, searching for them may become a feasible, additional criterion in donor selection. (Blood. 2015;125(20):3173-3182)

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Haploidentical hematopoietic transplantation from KIR ligand–mismatched donors with activating KIRs reduces nonrelapse mortality

Mancusi¹,

Ruggeri²,

Urbani³

et al. 2015

Blood

103

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“…In addition, several new variants of the activating receptor KIR2DS4 were discovered. KIR2DS4 is unique in that alleles either encode a membrane-associated form of the protein or a deletion variant that potentially encodes a secreted protein lacking the D2, stem, transmembrane, and cytoplasmic regions (25,26). We have identified new variants of both types of 2DS4 alleles, demonstrating that more than one allele encoding the deletion variant exists in the human population (Table II).…”

Section: Identification and Characterization Of New Kir Allelesmentioning

confidence: 96%

Activation of a Subset of Human NK Cells upon Contact with Plasmodium falciparum-Infected Erythrocytes

Artavanis‐Tsakonas

Eleme

McQueen

et al. 2003

The Journal of Immunology

178

183

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Human NK cells are the earliest source of the protective cytokine IFN-γ when PBMC from nonimmune donors are exposed to Plasmodium falciparum-infected RBC (iRBC) in vitro. In this study, we show that human NK cells form stable conjugates with iRBC but not with uninfected RBC and that induction of IFN-γ synthesis is dependent on direct contact between the NK cell and the iRBC. NK cells respond to iRBC only in the presence of a source of IL-12/IL-18 and the subset of NK cells that preferentially respond to iRBC express high levels of the lectin-like receptor CD94/NKG2A. There is heterogeneity between donors in their ability to respond to iRBC. DNA analysis has revealed considerable heterogeneity of killer Ig-like receptor (KIR) genotype among the donor population and has identified 21 new KIR allelic variants in the donors of African and Asian descent. Importantly, we find evidence for significant associations between KIR genotype and NK responsiveness to iRBC. This emphasizes the need for large-scale population-based studies to address associations between KIR genotype and susceptibility to malaria.

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“…Except for one variant of KIR3DP1, transcripts of these pseudogenes have not been detected (21). Several KIR2DL4 and KIR2DS4 alleles contain frameshift mutations that prematurely truncate the encoded receptor product (22)(23)(24). In other instances, it is difficult to predict whether genetic polymorphism affects KIR structure or expression.…”

mentioning

confidence: 99%

A Single Polymorphism Disrupts the Killer Ig-Like Receptor 2DL2/2DL3 D1 Domain

VandenBussche

Dakshanamurthy

Posch

et al. 2006

The Journal of Immunology

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Genetic polymorphisms found in the killer Ig-like receptor (KIR), two domains, long cytoplasmic tail 2/3 (KIR2DL2/3) locus are responsible for the differential binding of KIR2DL2/3 allelic products with their HLA-C ligands and have been associated with the resolution of hepatitis C infection. In our study, a KIR CD3ζ fusion-binding assay did not detect any interaction between the KIR2DL2*004 extracellular domain and several putative KIR2DL2/3 ligands. To determine the amino acid polymorphism(s) responsible for the KIR2DL2*004 phenotype, we mutated the polymorphic residues of full-length KIR and expressed them in human Jurkat cells. Flow cytometry analysis failed to detect the surface expression of receptors containing a threonine at position 41 (T41), a polymorphism specific to KIR2DL2*004. Confocal microscopy showed that receptors containing T41 were retained inside the cell and had a perinuclear localization, possibly indicating that their extracellular domain was misfolded. Most KIR2DL2/3 alleles possess an arginine at position 41 (R41), and we predicted through molecular modeling and demonstrated by mutagenesis that R41 most likely interacts with the nearby residues Y77 and D47. Interaction between these residues would maintain C strand contact with the C′ and F strands of the D1 domain β-sheet. Furthermore, R41 and Y77 are conserved in the C and F strand amino acid alignments of Ig-like superfamily members, and may therefore be necessary for the structural integrity of other immune response proteins. Our data indicate that the extracellular T41 polymorphism encoded by the KIR2DL2*004 allele most likely results in misfolding of the D1 domain and complete intracellular retention of the receptor.

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A common KIR2DS4 deletion variant in the human that predicts a soluble KIR molecule analogous to the KIR1D molecule observed in the rhesus monkey

Cited by 128 publications

References 21 publications

Haploidentical hematopoietic transplantation from KIR ligand–mismatched donors with activating KIRs reduces nonrelapse mortality

Haploidentical hematopoietic transplantation from KIR ligand–mismatched donors with activating KIRs reduces nonrelapse mortality

Activation of a Subset of Human NK Cells upon Contact with Plasmodium falciparum-Infected Erythrocytes

A Single Polymorphism Disrupts the Killer Ig-Like Receptor 2DL2/2DL3 D1 Domain

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