Origin and differentiation of KIR⁺ alloreactive NK cells in the haplo-HSCT setting. (A) In haplo-HSCT, large numbers of CD34⁺ isolated from the donor are infused in the patient after the conditioning regimen. NK cells are the first lymphoid cells to appear in peripheral blood shortly after engraftment. The first wave of NK cells expresses the HLA-E-specific CD94-NKG2A inhibitory receptor. Appearance of KIR⁺ cells in peripheral blood requires 4 to 6 additional weeks. (B) KIR⁺ NK cells may contain alloreactive NK cells (ie, cells that express KIR specific for HLA ligands not expressed by the recipient). Alloreactive NK cells efficiently kill leukemia blasts. This would mean that they have been “licensed,” even in an allogeneic recipient. This may be explained by the fact that the “megadoses” of donor HSCs infused may build up a BM microenvironment that is largely of donor type.