Taking license with natural killer cell maturation and repertoire development

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Abstract
Summary:  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.