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ABSTRACT: Human NK cells are the earliest source of the protective cytokine IFN-gamma 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-gamma 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.
The Journal of Immunology 12/2003; 171(10):5396-405. · 5.79 Impact Factor
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ABSTRACT: Interactions between killer immunoglobulin-like receptors (KIRs) and human leukocyte antigen (HLA) class I ligands influence development of natural killer (NK) cell repertoire and response to infection, cancer, and allogeneic tissue. As KIRs and HLA class I molecules are highly polymorphic, clinical allogeneic hematopoietic cell transplantation is predicted to frequently involve KIR mismatch, and thus to provide a unique system for study of human NK cell receptor repertoire development. Eighteen leukemia patients undergoing HLA-matched transplantation and their donors were analyzed for KIR genotype. Ten of 13 HLA-identical donor-patient pairs were KIR mismatched and 3 were matched; all HLA-matched unrelated pairs were KIR mismatched. Reconstitution of recipient NK cell repertoire following transplantation was examined using flow cytometry and monoclonal antibodies specific for KIR and CD94:NKG2A. These data form 3 groups. Six to 9 months after transplantation, 8 patients (group 1) reconstituted an NK cell repertoire resembling that of their donor, and for KIR-mismatched transplants, distinct from the recipient before transplantation. In the first year after transplantation, 5 patients (group 2) exhibited a generally depressed frequency of KIR-expressing NK cells and concomitant high frequency of CD94:NKG2A expression. By 3 years after transplantation, the frequency of KIR-expressing NK cells had increased to donor values, in the 3 patients from group 2 analyzed for this period. The remaining 5 patients experienced severe clinical complications following transplantation and displayed unique features in their NK cell receptor reconstitution. These results demonstrate that a majority of HLA-matched hematopoietic cell transplantations involve KIR mismatch and reveal differences in NK cell repertoire having potential impact for immune responsiveness and transplantation outcome.
Blood 06/2003; 101(9):3730-40. · 9.90 Impact Factor
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ABSTRACT: Genomic DNA from a panel of 41 healthy unrelated Japanese individuals was typed for the presence or absence of 16 KIR genes and pseudogenes. Only eight different KIR genotypes were found. Group A haplotypes outnumbered group B haplotypes in frequency by approximately 3:1, with individuals having two group A haplotypes accounting for 56% of the panel. The frequency of A haplotypes in the Japanese is higher than that observed in other populations. Flow cytometric comparison of KIR expression in 19 panel members showed considerable diversity in NK cell repertoire, which was also seen within the group of individuals having two A haplotypes. This diversity is likely due to allelic polymorphism in expressed genes of the A haplotype. In comparison to other populations, the Japanese appear less heterogeneous in KIR genotype as assessed by gene content.
Immunogenetics 12/2002; 54(8):543-50. · 2.93 Impact Factor
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ABSTRACT: Through differential killer cell Ig-like receptor (KIR) and CD94:NKG2 gene expression, human NK cells generate diverse repertoires, each cell having an inhibitory receptor for autologous HLA class I. Using a new method for measuring repertoire difference that integrates multiple flow cytometry parameters, we found individual repertoire stability, but population variability. Correlating repertoire differences with KIR and HLA genotype for 85 sibling pairs reveals the dominant influence of KIR genotype; HLA genotype having a subtle, modulating effect on relative KIR expression frequencies. HLA and/or KIR genotype also influences CD94:NKG2A expression. After HLA-matched stem cell transplantation, KIR repertoires either recapitulated that of the donor or were generally depressed for KIR expression. Human NK cell repertoires are defined by combinations of variable KIR and HLA class I genes and conserved CD94:NKG2 genes.
The Journal of Immunology 08/2002; 169(1):239-47. · 5.79 Impact Factor
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ABSTRACT: Killer Ig-like receptor (KIR) genes are a multigene family on human chromosome 19. KIR genes occur in various combinations on different haplotypes. Additionally, KIR genes are polymorphic. To examine how allelic polymorphism diversifies KIR haplotypes with similar or identical combinations of KIR genes, we devised methods for discriminating alleles of KIR2DL1, -2DL3, -3DL1, and -3DL2. These methods were applied to 143 individuals from 34 families to define 98 independent KIR haplotypes at the allele level. Three novel 3DL2 alleles and a chimeric 3DL1/3DL2 sequence were also identified. Among the A group haplotypes were 22 different combinations of 2DL1, 2DL3, 3DL1, and 3DL2 alleles. Among the B group haplotypes that were unambiguously determined were 15 distinct haplotypes involving 9 different combinations of KIR genes. A and B haplotypes both exhibit strong linkage disequilibrium (LD) between 2DL1 and 2DL3 alleles, and between 3DL1 and 3DL2 alleles. In contrast, there was little LD between the 2DL1/2DL3 and 3DL1/3DL2 pairs that define the two halves of the KIR gene complex. The synergistic combination of allelic polymorphism and variable gene content individualize KIR genotype to an extent where unrelated individuals almost always have different KIR types. This level of diversity likely reflects strong pressure from pathogens on the human NK cell response.
The Journal of Immunology 04/2002; 168(5):2307-15. · 5.79 Impact Factor
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ABSTRACT: HLA and KIR are diverse and rapidly evolving gene complexes that work together in human immunity mediated by cytolytic lymphocytes. Understanding their complex immunogenetic interaction requires study of both HLA and KIR diversity in the same human population. Here a panel of 72 unrelated north Indian Hindus was analyzed. HLA- A, B, C, DRB1, DQA1, and DQB1 alleles and their frequencies were determined by sequencing or high-resolution typing of genomic DNA; KIR genotypes were determined by gene-specific typing and by allele-level DNA typing for KIR2DL1, 2DL3, 2DL5, 3DL1, and 3DL2. From HLA analysis, the north Indian population is seen to have several characteristics shared either with Caucasian or East Asian populations, consistent with the demographic history of north India, as well as specific features, including several alleles at high frequency that are rare or absent in other populations. A majority of the north Indian KIR gene profiles have not been seen in Caucasian and Asian populations. Most striking is a higher frequency of the B group of KIR haplotypes, resulting in equal frequencies for A and B group haplotypes in north Indians. All 72 members of the north Indian panel have different HLA genotype and different KIR genotype.
Immunogenetics 04/2002; 53(12):1009-19. · 2.93 Impact Factor
