H-2D ligand expression by Ly49A⁺ natural killer (NK) cells precludes ligand uptake from environmental cells: Implications for NK cell function

To study the adaptation of natural killer (NK) cells to their major histocompatibility complex (MHC) class I environment we have established a novel mouse model with mosaic expression of H-2D^d using a Cre/loxP system. In these mice, we noticed that NK cells expressing the inhibitory receptor for D^d, Ly49A, were specifically underrepresented among cells with low D^d levels. That was due to the acquisition of D^d molecules by the Ly49A⁺ NK cells that have lost their D^d transgene. The uptake of H-2D molecules via the Ly49A receptor was restricted to strong ligands of Ly49A. Surprisingly, when Ly49A⁺ NK cells were D^d+, uptake of the alternative ligand D^k was not detectable. Similarly, one anti-Ly49A mAb (A1) bound inefficiently when Ly49A was expressed on D^d+ NK cells. Concomitantly, functional assays demonstrated a reduced capacity of Ly49A to inhibit H-2^bD^d as compared with H-2^b NK cells, rendering Ly49A⁺ NK cells in D^d+ mice particularly reactive. Minor reductions of D^d levels and/or increases of activating ligands on environmental cells may thus suffice to abrogate Ly49A-mediated NK cell inhibition. The mechanistic explanation for all these phenomena is likely the partial masking of Ly49A by D^d on the same cell via a lateral binding site in the H-2D^d molecule.