KIR Ligands Research Articles

Plasticity in the organization and sequences of human KIR/ILT gene families.

The approximately 1-Mb leukocyte receptor complex at 19q13.4 is a key polymorphic immunoregion containing all of the natural killer-receptor KIR and related ILT genes. When the organization of the leukocyte receptor complex was compared from two haplotypes, the gene content in the KIR region varied dramatically, with framework loci flanking regions of widely variable gene content. The ILT genes were more stable in number except for ILT6, which was present only in one haplotype. Analysis of Alu repeats and comparison of KIR gene sequences, which are over 90% identical, are consistent with a recent origin. KIR genesis was followed by extensive duplication/deletion as well as intergenic sequence exchange, reminiscent of MHC class I genes, which provide KIR ligands.

Independent contributions of HLA epitopes and killer inhibitory receptor expression to the functional alloreactive specificity of natural killer cells

Human NK cells express receptors (KIR) which inhibit lysis through binding to HLA class I on target cells. KIR expression in different individuals has not been intensively investigated and it is not known how the KIR repertoire relates to HLA type or influences the overall activity of NK populations. This may be important in the response of NK cells to HLA-mismatched organ transplants since the ligands for KIR are supertypic epitopes shared between certain HLA alleles. We studied the effect of matching for HLA on the cytotoxicity of NK cells from individuals homozygous or heterozygous for relevant HLA class I epitopes and correlated this with KIR expression and genotype. Considerable variation in the KIR repertoire of different donors was evident, including functional KIR expressed in the absence of specific HLA ligands. We confirmed the predominant influence of HLA-C in a hierarchy of inhibitory effects mediated by HLA class I loci. In certain individuals, inhibition patterns are more complicated and may be due to the relative expression of the CD94/NKG2 receptors. Our study reveals the separate contributions of HLA and KIR molecules to NK cell alloreactivity and provides a basis for consideration of the functional diversity of KIR genes in transplantation.

Functionally and Structurally Distinct NK Cell Receptor Repertoires in the Peripheral Blood of Two Human Donors

The expression of KIR and CD94:NKG2 receptors was determined for more than 100 natural killer (NK) cell clones obtained from two blood donors who differ in their HLA class I and KIR genes. More than 98% of the clones were inhibited by individual autologous class I allotypes, and every clone was inhibited by the combination of autologous allotypes. The patterns of inhibition correlate with expression of inhibitory receptors of defined specificity. One donor possesses three class I ligands for KIR, and a majority of NK cells use KIR as their inhibitory receptor; the second donor possesses only a single ligand for KIR, and a majority of NK cells use the more broadly reactive CD94:NKG2a as their inhibitory receptor. Because of these differences, the first donor has subpopulations of NK cells that kill cells of the second donor, whereas the NK cells of the second donor are universally tolerant of cells from the first donor.