This study investigates the inhibitory effects of mesenchymal stem cells (MSCs) on natural killer (NK) cells and the underlying mechanisms. The authors found that MSCs not only inhibit the cytokine-induced proliferation of freshly isolated NK cells but also prevent the induction of effector functions such as cytotoxic activity and cytokine production. This inhibitory effect is associated with a significant down-regulation of the surface expression of activating NK receptors NKP30, NKP44, and NKG2D. The study also demonstrates that indoleamine 2,3-dioxygenase (IDO) and prostaglandin E2 (PGE2) are key mediators of the MSC-induced inhibition of NK cells. Specifically, the simultaneous blocking of IDO and PGE2 almost completely restores NK cell proliferation and cytotoxic activity. These findings suggest that MSCs can significantly suppress NK cell functions, which may have implications for the use of MSCs in hematopoietic stem cell transplantation (HSCT) and adoptive immunotherapy.This study investigates the inhibitory effects of mesenchymal stem cells (MSCs) on natural killer (NK) cells and the underlying mechanisms. The authors found that MSCs not only inhibit the cytokine-induced proliferation of freshly isolated NK cells but also prevent the induction of effector functions such as cytotoxic activity and cytokine production. This inhibitory effect is associated with a significant down-regulation of the surface expression of activating NK receptors NKP30, NKP44, and NKG2D. The study also demonstrates that indoleamine 2,3-dioxygenase (IDO) and prostaglandin E2 (PGE2) are key mediators of the MSC-induced inhibition of NK cells. Specifically, the simultaneous blocking of IDO and PGE2 almost completely restores NK cell proliferation and cytotoxic activity. These findings suggest that MSCs can significantly suppress NK cell functions, which may have implications for the use of MSCs in hematopoietic stem cell transplantation (HSCT) and adoptive immunotherapy.