Regulation of the Natural Killer Cell Receptor Repertoire

Natural killer cells express inhibitory receptors specific for MHC class I proteins and stimulatory receptors with diverse specificities. The MHC-specific receptors discriminate among different MHC class I alleles and are expressed in a variegated, overlapping fashion, such that each NK cell expresses several inhibitory and stimulatory receptors. Evidence suggests that individual developing NK cells initiate expression of inhibitory receptor genes in a sequential, cumulative, and stochastic fashion. Superimposed on the receptor acquisition process are multiple education mechanisms, which act to coordinate the stimulatory and inhibitory specificities of developing NK cells. One process influences the complement of receptors expressed by individual NK cells. Other mechanisms may prevent NK cell autoaggression even when the developing NK cell fails to express self-MHC-specific inhibitory receptors. Together, these mechanisms ensure a self-tolerant and maximally discriminating NK cell population. Like NK cells, a fraction of memory phenotype CD8⁺ T cells, as well as other T cell subsets, express inhibitory class I–specific receptors in a variegated, overlapping fashion. The characteristics of these cells suggest that inhibitory receptor expression may be a response to prior antigenic stimulation as well as to poorly defined additional signals. A unifying hypothesis is that both NK cells and certain T cell subsets initiate expression of inhibitory receptors in response to stimulation.