Tuning of human NK cells by endogenous HLA-C expression

NK cells are primarily responsible for detecting malignant or pathogen-infected cells, and their function is influenced both by stress-associated activating signals and opposing inhibitory signals from receptors that recognize self MHC. The receptors that produce this inhibitory signal shift from the NKG2A:HLA-E system to that of KIR:HLA as the NK cells mature. This maturation is associated with an increase in lytic activity, as well as an increase in HLA-C protein levels controlled by the NK-specific HLA-C promoter, NK-Pro. We propose that modulation of the translatability of HLA-C transcripts in NK cells constitutes an evolutionary mechanism to control cis inhibitory signaling by HLA-C, which fine tunes NK cell activity. Furthermore, the high degree of variability in KIR receptor affinity for HLA alleles, as well as the variable expression levels of both KIR and HLA, suggest an evolutionary requirement for the tuning of NK lytic activity. Various data have demonstrated that mature NK cells may gain or lose lytic activity when placed in different environments. This indicates that NK cell activity may be more a function of constant tuning by inhibitory signals, rather than a static, irreversible “license to kill” granted to mature NK cells. Inhibitory signaling controls the filling of the cytolytic granule reservoir, which becomes depleted if there are insufficient inhibitory signals, leading to a hyporesponsive NK cell. We propose a novel model for the tuning of human NK cell activity via cis interactions in the context of recent findings on the mechanism of NK education.