Estimation of the Size of the Alloreactive NK Cell Repertoire: Studies in Individuals Homozygous for the Group A <i>KIR</i> Haplotype

Fauriat, Cyril; Andersson, Sandra; Björklund, Andreas; Carlsten, Mattias; Schaffer, Marie; Björkström, Niklas K.; Baumann, Bettina C.; Michaëlsson, Jakob; Ljunggren, Hans‐Gustaf; Malmberg, Karl‐Johan

doi:10.4049/jimmunol.181.9.6010

Cited by 103 publications

(122 citation statements)

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“…Therefore, the selection of optimal donors is based, at the molecular level, on the analysis of donor KIR gene profile and of donor and recipient HLA class I typing. Importantly, recent data have demonstrated that, using combinations of different anti-KIR mAb, it is possible to define the size of the alloreactive NK cell subset (14,(36)(37)(38)(39)(40). Our present data indicate that the evaluation of the pool size of alloreactive NK cells in HSCT can only be possible by the use of appropriate mAb combination.…”

Section: Discussionmentioning

confidence: 56%

“…The presence of alloreactive NK cells can be predicted by the analysis of the donor KIR gene profile and by the HLA class I typing of both donor and recipient. The actual presence and size of the alloreactive NK subset can be assessed by cytofluorimetric analysis using appropriate combinations of anti-KIR mAb (14,(36)(37)(38)(39)(40). In these experiments, alloreactive NK cells are identified as a subset expressing iKIRs specific for the mismatched KIR ligand but missing all the other iKIRs and NKG2A.…”

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confidence: 99%

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Combined Genotypic and Phenotypic Killer Cell Ig-Like Receptor Analyses Reveal KIR2DL3 Alleles Displaying Unexpected Monoclonal Antibody Reactivity: Identification of the Amino Acid Residues Critical for Staining

Falco

Romeo

Marcenaro³

et al. 2010

The Journal of Immunology

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In humans, recent clinical and experimental data from hematopoietic stem cell transplantation revealed that donor-derived alloreactive NK cells exert a beneficial graft versus leukemia effect. The existence of donor-derived alloreactive NK cells can be predicted on the basis of donor killer cell Ig-like receptor (KIR) gene profile and HLA class I typing of both donor and recipient. Moreover, the size of the alloreactive NK cell population can be directly assessed by the combined use of anti–KIR-specific mAb. In this study, in an attempt to improve the definition of alloreactive NK cell subsets, we assessed the KIR genotype and phenotype in a cohort of 44 donors. This approach allowed the identification of two different KIR2DL3 alleles (KIR2DL3*005 and the novel allele KIR2DL3*015) that did not react with the anti–KIR2DL3-specific ECM41 mAb. In contrast, both alleles were recognized at the cell surface by several mAb reacting with KIR2DL2/L3/S2. Notably, KIR2DL3*005 was also stained by the anti–KIR2DL1/S1-specific EB6B and 11PB6 mAb. Functional analysis revealed that, despite its particular mAb reactivity, the specificity of KIR2DL3*005 for HLA-C molecules did not differ from that of other KIR2DL2/L3 alleles. Finally, site-directed mutagenesis demonstrated that glutamine at position 35 is required for ECM41 staining, whereas glutamic acid 35 and arginine 50 are relevant for staining with EB6B or 11PB6 mAb. Our present data represent a substantial progress in the characterization of the NK cell repertoire and an improved phenotypic/functional definition of given KIR+ subsets.

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Section: Discussionmentioning

confidence: 56%

mentioning

confidence: 99%

Combined Genotypic and Phenotypic Killer Cell Ig-Like Receptor Analyses Reveal KIR2DL3 Alleles Displaying Unexpected Monoclonal Antibody Reactivity: Identification of the Amino Acid Residues Critical for Staining

Falco

Romeo

Marcenaro³

et al. 2010

The Journal of Immunology

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“…During NK cell development, interactions between C1, C2, and Bw4 and cognate KIR determine the strength with which mature NK cells respond to cells whose HLA class I expression is perturbed by disease, a developmental process termed NK cell education (22). The A3/A11 epitope contributes little to NK cell education (23,24), a distinction that correlates with the exceptionally high sensitivity of KIR3DL2 to the peptide bound by HLA-A*03 or A*11 (21).…”

Section: Resultsmentioning

confidence: 99%

Co-evolution of KIR2DL3 with HLA-C in a human population retaining minimal essential diversity of KIR and HLA class I ligands

Gendzekhadze

Norman

Abi-Rached

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

111

178

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Natural killer (NK) cells contribute to immunity and reproduction.Guiding these functions, and NK cell education, are killer cell Ig-like receptors (KIR), NK cell receptors that recognize HLA class I. In most human populations, these highly polymorphic receptors and ligands combine with extraordinary diversity. To assess how much of this diversity is necessary, we studied KIR and HLA class I at high resolution in the Yucpa, a small South Amerindian population that survived an approximate 15,000-year history of population bottleneck and epidemic infection, including recent viral hepatitis. The Yucpa retain the three major HLA epitopes recognized by KIR. Through balancing selection on a few divergent haplotypes the Yucpa maintain much of the KIR variation found worldwide. HLA-C*07, the strongest educator of C1-specific NK cells, has reached unusually high frequency in the Yucpa. Concomitantly, weaker variants of the C1 receptor, KIR2DL3, were selected and have largely replaced the form of KIR2DL3 brought by the original migrants from Asia. HLA-C1 and KIR2DL3 homozygosity has previously been correlated with resistance to viral hepatitis. Selection of weaker forms of KIR2DL3 in the Yucpa can be seen as compensation for the high frequency of the potent HLA-C*07 ligand. This study provides an estimate of the minimal KIR-HLA system essential for long-term survival of a human population. That it contains all functional elements of KIR diversity worldwide, attests to the competitive advantage it provides, not only for surviving epidemic infections, but also for rebuilding populations once infection has passed.Amerindian ͉ immune diversity ͉ natural selection ͉ NK cells ͉ reproduction

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“…Functional education of human NK cells by HLA class I is well established (13,15,(39)(40)(41)(42), and a quantitative influence of HLA on NK cell responsiveness may explain, for example, how a single nucleotide polymorphism associated with a higher HLA-C expression levels is beneficial in acute HIV infection (43,44). The role of HLA class I molecules on the human NK cell repertoire is less clear, but is implied from studies showing that specific compound genotypes of KIR and HLA may provide protection or susceptibility to infections, cancers, and successful pregnancy (45).…”

Section: Discussionmentioning

confidence: 99%

Skewing of the NK Cell Repertoire by MHC Class I via Quantitatively Controlled Enrichment and Contraction of Specific Ly49 Subsets

Brodin

Lakshmikanth

Kärre

et al. 2012

The Journal of Immunology

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A major task for the immune system is to secure powerful immune reactions while preserving self-tolerance. This process is particularly challenging for NK cells, for which tolerizing inhibitory receptors for self-MHC class I is both cross-reactive and expressed in an overlapping fashion between NK cells. We show in this study that during an education process, self-MHC class I molecules enrich for potentially useful and contract potentially dangerous NK cell subsets. These processes were quantitatively controlled by the expression level of the educating MHC class I allele, correlated with susceptibility to IL-15 and sensitivity to apoptosis in relevant NK cell subsets, and were linked to their functional education. Controlling the size of NK cell subsets with unique compositions of inhibitory receptors may represent one mechanism by which self-MHC class I molecules generate a population of tolerant NK cells optimally suited for efficient missing self-recognition.

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Estimation of the Size of the Alloreactive NK Cell Repertoire: Studies in Individuals Homozygous for the Group A KIR Haplotype

Cited by 103 publications

References 65 publications

Combined Genotypic and Phenotypic Killer Cell Ig-Like Receptor Analyses Reveal KIR2DL3 Alleles Displaying Unexpected Monoclonal Antibody Reactivity: Identification of the Amino Acid Residues Critical for Staining

Combined Genotypic and Phenotypic Killer Cell Ig-Like Receptor Analyses Reveal KIR2DL3 Alleles Displaying Unexpected Monoclonal Antibody Reactivity: Identification of the Amino Acid Residues Critical for Staining

Co-evolution of KIR2DL3 with HLA-C in a human population retaining minimal essential diversity of KIR and HLA class I ligands

Skewing of the NK Cell Repertoire by MHC Class I via Quantitatively Controlled Enrichment and Contraction of Specific Ly49 Subsets

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