Current perspectives of natural killer cell education by MHC class I molecules

Natural killer (NK) cells are negatively controlled by MHC class I molecules, which are recognized through inhibitory receptors. The main type of inhibitory receptors are Ly49 receptors (in mice) and killer cell immunoglobulin-like receptors (KIRs; in humans). When target cells downregulate MHC class I molecule expression, they have a 'missing-self' phenotype that is recognized by NK cells and results in their activation.MHC class I molecules are also necessary for the functional development of NK cells. This process is termed 'NK cell education' and has also been referred to as 'licensing' or 'arming'. NK cells that lack inhibitory receptors or only express inhibitory receptors for which no MHC class I ligands are expressed in vivo are uneducated and hyporesponsive.Successful NK cell education leads to the full functional development of NK cells, including the ability to mediate cytotoxicity and cytokine secretion. Individual NK cells are also sensitive to the strength of inhibitory input during education and set thresholds for activation that match this inhibitory input.The signalling mechanisms that link the inhibitory input to functional development during NK cell education are unknown. It has also not been determined whether NK cell education is restricted to haematopoietic niches in the body and requires interactions with a particular cell, or whether it can occur everywhere after interaction with any surrounding self cell.Individual Ly49 receptors and KIRs are expressed in a stochastic and independent manner on NK cells. This leads to the formation of a unique 'NK cell repertoire' in each individual, which is characterized by the coexistence of several NK cell subsets, each expressing from zero to five receptors.The composition of the NK cell repertoire is determined by several factors, most of which have yet to be identified. In mice, the MHC repertoire affects the composition of the final Ly49 repertoire and thus contributes to NK cell education. A similar effect of the MHC repertoire on the human NK cell repertoire is less obvious.NK cells may contribute to clinically important graft-versus-leukaemia effects following stem cell transplantation, in particular against acute myeloid leukaemia. A better understanding of NK cell education may help clinicians to find the optimal donor for each recipient, based on an analysis of their KIRs and MHC repertoire.