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 histo compatibility 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 Dd 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 Dd+, uptake of the alternative ligand D-k was not detectable. Similarly, one anti-Ly49A mAb (A1) bound inefficiently when Ly49A was expressed on Dd+ NK cells. Concomitantly, functional assays demonstrated a reduced capacity of Ly49A to inhibit H-2(b)D(d) as compared with H-2(b) NK cells, rendering Ly49A(+) NK cells in Dd+ 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.