Target recognition, tolerance, missing self. (A) NK cells recognize and kill their targets by an integrated balance of inhibitory and activating signals to discriminate between healthy cells (tolerance) vs elimination of transformed or virally infected targets (killing). NK-cell tolerance depends on several major histocompatibility complex (MHC) class I inhibitory signals (either classical, HLA-A, -B or -C, or nonclassical, HLA-E) expressed by heathy cells that engage KIR or NKG2A with minimal activation signals resulting in tolerance. Malignant transformation or viral infection promotes target cell killing by downregulation of MHC class I expression and an upregulation of signals from activating NK-cell receptors. (B) Although in some cases, MHC downregulation is variable or incomplete, target cell killing can still occur by changing the balance with activating signals upregulated by stress-induced activating receptor ligands. (C) This balance between inhibition and activation can be uniquely manipulated in the hematopoietic transplant setting by selection of donors who will respond to apparent missing self HLA class I in the HLA-mismatched recipients. For example, reconstitution with a high frequency of donor KIR2DL1⁺ NK cells would not be inhibited in a HLA-C1 (C1⁺-HLA-C) recipient (KIR ligand mismatch). Here, NK-cell alloreactivity would kill the recipient’s tumor. In contrast, when the same KIR2DL1⁺ NK cells reconstitute in an HLA-C2 recipient (C2⁺-HLA-C) (KIR ligand match), the recipient’s tumor would be seen as having self HLA class I and would not provoke an alloreactive NK-cell response.