| Natural killer (NK) cells express cell surface receptors that recognize polymorphic determinants of major histocompatibility complex (MHC) molecules and inhibit NK cell activity. In humans, differential expression of killer cell Ig-like receptors (KIR) and CD94:NKG2 by NK cells creates diverse repertoires, each cell having an inhibitory receptor for autologous class I human leukocyte antigens (HLA). This apparent adaptation of NK cell receptor repertoire to MHC environment has been difficult to reconcile, however, with evidence that KIR expression is controlled by non-HLA genetic elements.; KIR population diversity makes the KIR locus itself a candidate for the non-HLA genes controlling KIR phenotype. To examine how allelic polymorphism diversifies haplotypes having matching sets of KIR genes, PCR subtyping methods were designed to discriminate alleles of KIR2DL1, 2DL3, 3DL1, and 3DL2. These were applied to 143 individuals from 34 families to define 98 parental KIR haplotypes. Among these were A group haplotypes having 22 different combinations of 2DL1, 2DL3, 3DL1, and 3DL2 alleles, and 15 distinct B group haplotypes involving 9 different sets of KIR genes. The synergistic combination of allelic polymorphism and variable gene content individualize KIR genotype such that unrelated individuals are rarely KIR-matched.; Using a new method for measuring KIR repertoire difference that integrates multiple flow cytometry parameters, the hypothesis that KIR genotype controls KIR phenotype was tested by: (1) comparing KIR and CD94:NKG2 expression in healthy siblings pairs of known HLA and KIR type, and (2) by following KIR repertoire reconstitution after allogeneic, HLA-matched stem cell transplantation. Correlating repertoire differences with KIR and HLA genotype for 85 sibling pairs revealed the dominant influence of KIR genotype; HLA having a subtle, modulating effect on relative frequencies of KIR-expressing cells. HLA and KIR genotype also influenced CD94:NKG2A expression, and frequencies of CD94:NKG2A and KIR-expressing cells were inversely correlated. After HLA-matched transplantation, reconstituted KIR repertoires either recapitulated that of the donor, or showed a general depression in KIR expression. Human NK cell repertoires appear genetically predetermined, defined by combinations of variable KIR and class I HLA genes and conserved CD94:NKG2 genes. |
