Schematic of hybrid resistance. (A) The classic model for hybrid resistance occurs when a subset of F1 NK cells does not express an inhibitory receptor for parental MHC. Here, missing self-recognition is sufficient to promote BM rejection. (B) Hybrid resistance is prevented when inhibitory receptors on F1 NK cells react with parental MHC and inhibit activation by missing self-recognition. (C) Additional pathways of rejection can occur when NKG2D is engaged on the F1 NK cell, even in the presence of inhibitory signals from binding parental MHC (i). In some subsets of NK cells, 2 additional activating signals (NKG2D and an activating Ly49) are required to overcome the inhibitory receptor signals in F1 NK cells resulting from interactions with parental MHC (ii).