Evidence of a natural killer (NK) cell repertoire for (allo) antigen recognition: definition of five distinct NK-determined allospecificities in humans.

Abstract

Sllmm~Previous studies indicated that CD3-CD16 + natural killer (NK) cells are capable of specific alloantigen recognition. Thus, alloreactive NK clones lysed normal aUogeneic target cells (phytohemagglutinin [PHA] blasts) bearing the stimulating alloantigen but did not lyse autologous cells or the majority of unrelated allogeneic cells. In this study we investigated whether NK cells isolated from single individuals could exhibit different aUospecifcities. To this end, we derived large numbers of CD3-CD16 + clones (in the presence of PHA) from fresh CD3-peripheral blood lymphocytes. Cloning effciencies ranged between 5 and 10%. The resulting CD3-CD16 + clones were tested for their reactivity against a panel of allogeneic PHA blasts (derived from six donors). In a given individual (A), four distinct groups of clones could be identifed according to their pattern of reactivity (over 400 clones have been analyzed). Clones that could be assigned to one or another group of specificity represented 36% of all clones derived from this donor. The remaining clones did not display cytolytic activity against any of the aUogeneic target cells used in the panel. None of the clones lysed autologous (A) PHA blasts, yet, these cells were lysed by the representative clones G10 and H12 specific for donor A. Clones displaying a cytolytic pattern of reactivity identical to that defined for donor A were present in other individuals studied, however not all groups of allospecific clones were necessarily represented in different individuals. Allospecifc clones belonging to the various groups were homogeneous in the expression of EB6/GL183-triggering surface molecules, and could thus be assigned to one or another of the previously defined subsets of NK cells. Genetic analysis of the new NK-defined alloantigens was performed in representative families. The corresponding characters were found to segregate independently and, at least for three of them, an autosomic recessive type of inheritance could be demonstrated. Moreover, the comparative analysis of the segregation of the major histocompatibility complex haplotypes and the recessive or dominant alleles of the genes governing the five specificities analyzed indicated that there is no independent sampling between the two genetic traits, thus suggesting that the genes regulating the NK-defined specificities are carried by chromosome 6. Finally, some donors expressed more than one specificity, thus providing evidence for an NK-defined complex haplotype.

Evidence of a selective depletion of a CD16+ CD56+ CD8+ natural killer cell subset during HIV infection

“…It appears that the diminished NK-related cytotoxicity in HIV-infected patients results from the contribution of several concomitant factors (9). We suggest that the quantitative alterations that occur within the NK compartment might play an important role in the in vivo NK dysfunction, although more studies are required.…”

Identification of distal KIR promoters and transcripts

“…4 KIR expression is variegated, enabling NK cells to distinguish subtle changes in HLA expression. [5][6][7] Variegated expression is beneficial, since virus infection or transformation might only downregulate one HLA allele, and the presence of NK cells that express a subset of inhibitory HLA receptors allows the detection of cells that have altered expression of a single type of HLA molecule. Variation in the number and type of KIR genes present in an individual genotype leads to a wide array of KIR repertoires in the human population.…”

Cytolytic activity of NK cell clones against acute childhood precursor-B-cell leukaemia is influenced by HLA class I expression on blasts and the differential KIR phenotype of NK clones

“…12 The alloreactions of human NK cell clones have been defined mainly by the activity of inhibitory receptors with specificity for HLA class I determinants. 13,14 The killer cell Ig-like receptor (KIR) family includes inhibitory receptors for polymorphic determinants of HLA-A (KIR3DL2), HLA-B (KIR3DL1/CD158e) and HLA-C (KIR2DL1/ CD158a, KIR2DL2, KIR2DL3/CD158b). 15 In the absence of the cognate ligand, NK cells kill allogeneic target cells.…”