Enrichment and Contraction of Specific Ly49 Class I via Quantitatively Controlled Skewing of the NK Cell Repertoire by MHC

A major task for the immune system is to secure powerful immune reactions while preserving self-tolerance. This process is particularly challenging for NK cells, for which tolerizing inhibitory receptors for self-MHC class I is both cross-reactive and expressed in an overlapping fashion between NK cells. We show in this study that during an education process, self-MHC class I molecules enrich for potentially useful and contract potentially dangerous NK cell subsets. These processes were quantitatively controlled by the expression level of the educating MHC class I allele, correlated with susceptibility to IL-15 and sensitivity to apoptosis in relevant NK cell subsets, and were linked to their functional education. Controlling the size of NK cell subsets with unique compositions of inhibitory receptors may represent one mechanism by which self-MHC class I molecules generate a population of tolerant NK cells optimally suited for efficient missing self-recognition. N atural killer cell function is controlled by a balance between inhibitory and activating receptors. Activating receptors recognize a variety of ligands, some of which are induced by cellular stress (1). Murine Ly49 receptors and human killer Ig-like receptors (KIR) are the most well-studied inhibitory receptors. These recognize MHC class I molecules and prevent NK cell activation upon engagement. The NKG2A receptor recognizes nonclassical MHC class I molecules (Qa-1 b in mice and HLA-E in humans) containing peptides derived from classical MHC class I molecules (2). Thus, two parallel layers of MHC class I-mediated protection of normal cells exist (1). When such cells downregulate MHC class I expression, the protective self-ligand is lost for both layers, allowing the NK cell to mediate missing self-recognition (3, 4). To secure self-tolerance, yet allow for missing self-recognition when necessary, the NK cell system must be educated by self-MHC class I. This process includes two effects. The first controls development of functional potency in NK cells, resulting in a capacity to react against normal cells lacking MHC class I expression (3– 13). This effect depends on the expression of inhibitory Ly49/KIR or NKG2A receptors on NK cells, because NK cells lacking such receptors, or expressing inhibitory receptors for which no self-MHC class ligand is present, are hyporesponsive (11–13). Furthermore , functional education by MHC class I does not work as an on/off switch. Instead, an individual NK cell dynamically determines its threshold for activation based on the strength of inhibitory input (14–18). A second effect by MHC class I molecules on …