MHC-dependent Shaping of the Inhibitory Ly49 Receptor Repertoire on NK Cells: Evidence for a Regulated Sequential Model

Engagement of MHC class I-specific inhibitory receptors regulates natural killer (NK) cell development and function. Using both new and previously characterized anti-Ly49 monoclonal antibodies, we comprehensively determined expression and co-expression frequencies of four Ly49 receptors by NK cells from MHC-congenic, MHC class I-deficient, and Ly49A-transgenic mice to study mechanisms that shape the inhibitory Ly49 repertoire. All Ly49 receptors were expressed on partially overlapping subsets. Significantly, in the absence of class I MHC, several receptor pairs were co-expressed more frequently than predicted from a purely random expression model, indicating that biases independent of MHC class I underlie receptor co-expression in some cases. MHC interactions were found to inhibit Ly49 co-expression variably depending on the MHC allele and the receptor pair examined. These data extend previous evidence that interactions with MHC shape the repertoire. It was previously proposed that developing NK cells express Ly49 receptors sequentially and cumulatively, until self-MHC specific receptors are expressed and inhibit new receptor expression. Fulfilling a major prediction of this model, we found that class I recognition by a Ly49A transgene expressed by all developing NK cells equivalently inhibited expression of endogenous self-specific and nonself-specific Ly49 receptors.