NK cell education: not an on-off switch but a tunable rheostat

Heterogeneity in the natural killer (NK) cell population is determined by variegated expression of polygenic and polymorphic receptors and distinct phenotypes and functions of NK cell subsets. Here, we outline an additional heterogeneity at the level of MHC-dependent education of NK cells. Based on data obtained using polychromatic flow cytometry and mice with single MHC class I alleles, we argue that NK cell responsiveness is tuned along a continuum determined by the strength of the inhibitory input received by the individual NK cell during education. This model has implications for the use of NK cells in therapeutic settings and affects interpretations of how NK cells control virus infections and regulate autoimmunity.