Taking license with natural killer cell maturation and repertoire development

Combining population analysis with in-depth analysis of selected individuals, the tolerance of human natural killer (NK) cells to autologous major histocompatibility complex (MHC) class I and potential reactivity to allogeneic MHC class I have been studied. Analysis of NK cell clones in long-term culture and peripheral blood NK cells after short-term culture (20-24 h) shows that NK cell tolerance is determined by interactions of autologous MHC class I with CD94:NKG2A and inhibitory killer cell immunoglobulin-like receptors (KIRs). Alloreactivity is predicted whenever the donor of the allogeneic target lacks a cognate MHC class I-KIR, ligand-receptor pair that is present in the NK cell donor. In the human population, there is a wide variation in the NK cell repertoire of KIRs and CD94:NKG2A expression. Variation is principally due to KIR gene variation and polymorphism, with a smaller effect due to MHC class I. The presence of MHC class I increases the frequency of NK cells expressing the cognate KIR, an effect that is diminished by the presence of other cognate-ligand pairs. The minor influence of MHC class I on the KIR repertoire indicates that NK cell development is an efficient process in which the expression of inhibitory MHC class I receptors at the final stages ensures that functionally active human NK cells are self-tolerant.