Human Multipotent Adult Progenitor Cells (hMAPCs) are isolated from bone marrowwith more extensive expansion capacity compared to human Mesenchymal Stem Cells(hMSCs), and with the ability to differentiate into endothelium. Like hMSCs, hMAPCsinhibit T cell proliferation induced by alloantigens. In this study we tested theinteraction between hMAPCs and natural killer (NK) cells. We assessed thesusceptibility of hMAPCs to NK cell-mediated lysis and the immunomodulation ofhMAPCs on NK cell function during IL-2-driven stimulation and cytolytic effectorphase. Human MAPCs express the ligands PVR and ULBP-2/5/6, which are recognizedby activating NK cell receptors. However, they also express MHC class I molecules,which induce inhibitory signals in NK cells. Freshly isolated NK cells at differenteffector:target ratios did not kill hMAPCs as assessed by an MTT and 51Cr-releaseassay, while hMAPCs impaired the cytotoxic activity of resting NK cells against theNK-sensitive K562 leukemia cell line. By contrast, IL-2 stimulated NK cells werecapable of killing hMAPCs and pre-activated NK cells were not influenced during theircytotoxic effector function against K562 cells by hMAPCs. When added during the 6-day pre-activation phase with IL-2, hMAPCs dose-dependently reduced NK cellproliferation in an IDO-dependent manner, but they did not influence the induction ofcytotoxic capacity by IL-2. This study indicates that human MAPCs mutually interactwith NK cells.