H-2D Ligand Expression by Ly49A+ Natural Killer (NK) Cells Precludes Ligand Uptake from Environmental Cells

Abstract

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-2Dd using a Cre/loxP system. In these mice, we noticed that NK cells expressing the inhibitory receptor for Dd, Ly49A, were specifically underrepresented among cells with low Dd levels. That was due to the acquisition of Dd molecules by the Ly49A+ NK cells that have lost their Dd 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 Dk 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-2bDd as compared with H-2b NK cells, rendering Ly49A+ NK cells in Dd+ mice particularly reactive. Minor reductions of Dd 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 Dd on the same cell via a lateral binding site in the H-2Dd molecule.