Natural killer cell education in human health and disease

Abstract

Natural killer (NK) cells maintain immune homeostasis by detecting and eliminating damaged cells. Simultaneous activating and inhibitory input are integrated by NK cells, with the net signal prompting cytotoxicity and cytokine production, or inhibition. Chief among the inhibitory ligands for NK cells are 'self' human leukocyte antigen (HLA) molecules, which are sensed by killer immunoglobulin-like receptors (KIR). Through a process called 'education', the functional capabilities of each NK cell are counterbalanced by their sensitivity for inhibition by co-inherited 'self' HLA. HLA and their ligands, the killer immunoglobulin-like receptors (KIR), are encoded by polymorphic, polygenic gene loci that segregate independently, therefore, NK education and function differ even between related individuals. In this review, we describe how variation in NK education, reactivity and sensitivity for inhibition impacts reproductive success, infection, cancer, inflammatory and autoimmune diseases.

Figure 1. NK education and impacts on human health

NK cell education represents a continuum of reactivity and inhibition, determined by interactions with co-inherited HLA. Cells capable of high avidity binding exhibit the most potent “missing self” reactivity and sensitivity for inhibition by “self” HLA class I molecules. Uneducated NK cells do not bind “self” HLA molecules, leading to weak “missing self” capabilities, but also insensitivity for inhibition. NK education determines the threshold for NK reactivity, with the strength of NK education inversely correlated with the requirement for additional activating input (i.e. pro-inflammatory signals or bound antibodies). NK education equips populations to detect damaged cells exhibiting a variety of HLA phenotypes, with uneducated NK cells as the best effectors against HLA-expressing targets (i.e. most cancers) and educated NK cells as the best effectors against HLA-negative targets (i.e. certain viral infections). Successful pregnancy is fostered by specialized uterine NK cells (uNK), educated to enable trophoblast invasion and placentation, while managing fetal growth.