Schematic representation of the role of NKR-P1B:Clr-b recognition in NK cell function. Four different scenarios depicting NK cell function in the presence or absence of NKR-P1B:Clr-b recognition are shown. (A) Normal healthy cells express MHC-I and Clr-b, which are recognized by inhibitory Ly49 and NKR-P1B receptors on NK cells, respectively, resulting in their protection from NK cells. Normal MHC-I levels are sufficient to protect these cells from NKR-P1B-deficient NK cells. (B) WT NK cells kill Clr-b-deficient target cells through an MHC-I-independent missing-self response. NKR-P1B-deficient NK cells cannot sense Clr-b-deficiency on target cells. (C) WT NK cells efficiently kill MHC-I-deficient target cells through MHC-I-dependent missing-self recognition. NKR-P1B-deficient NK cells are more efficient in killing MHC-I-deficient cells, possibly due to lack of Clr-b-mediated inhibition and a higher dependence on MHC-I-mediated education. (D) B lymphoma cells express normal levels of MHC-I and Clr-b. Tumor cells also express ligands for activating NK cell receptors, making them susceptible to NK cells. In the absence of inhibitory NKR-P1B receptor signals, NK cells have improved immunosurveillance capacity against Clr-b-expressing tumor cells, which can escape immune detection by WT NK cells.