Self-tolerance of human natural killer cells lacking self-HLA-specific inhibitory receptors

Natural killer (NK) cells identify cells with altered human leucocyte antigen (HLA) expression as targets through lacking engagement of self-HLA-specific inhibitory receptors (e.g. killer cell immunoglobulin-like receptor, KIR). Thus, they eliminate cells with 'missing self' because of viral or malignant transformation. We performed analysis of HLA, KIR genotypes and KIR receptor expression patterns at single cell level in NK cells in 17 donors. The function of NK cell subsets is determined by degranulation assays using target cells expressing self, cognate, control or no HLA class I. Donors could be grouped into three groups: their NK cells possess potential for alloreactivity, autoreactivity based on the presence of NK cells expressing particular KIR only (mono-KIR) in the absence of its ligand or lack alloreactivity. All donors possess NK cells lacking all detectable inhibitory receptors. Both potential autoreactive subpopulations did not respond to HLA class I-positive target cells. They retain partial reactivity against HLA class I-negative tumour target cells. Mono-KIR NK cells without the corresponding ligands in the individuals and NK cells lacking all inhibitory receptors behave self-tolerant. Our results suggest alternative mechanisms than HLA-specific inhibitory receptors to control NK cell activity. But HLA seems to be involved in shaping effector function of the NK cell repertoire.