Quantifying the reduction in accessibility of the inhibitory NK cell receptor Ly49A caused by binding MHC class I proteins in cis

Murine natural killer (NK) cells are inhibited by target cell MHC class I molecules via Ly49 receptors. However, Ly49 receptors can be made inaccessible to target cell MHC class I by a cis interaction with its MHC class I ligand within the NK cell membrane. It has recently been demonstrated that MHC class I proteins transfer from the target cells to the NK cell. Here, we establish that the number of transferred MHC class I proteins is proportional to the number of Ly49A receptors at the NK cell surface. Ly49A+ NK cells from mice expressing the Ly49A ligand H‐2Dd showed a 90% reduction in Ly49A accessibility compared to Ly49A+ NK cells from H‐2Dd‐negative mice. The reduction was caused both by lower expression of Ly49A and interactions in cis between Ly49A and H‐2Dd at the NK cell surface. Approximately 75% of the Ly49A receptors on H‐2Dd‐expressing NK cells were occupied in cis with endogenous H‐2Dd and only 25% were free to interact with H‐2Dd molecules in trans. Thus, H‐2Dd ligands control Ly49A receptor accessibility through interactions both in cis and in trans.