At present, the definition of a mesenchymal stem cell (MSC) is based on the characteristics admitted by the International Society for Stem Cell Therapy (ISCT) . Indeed, MSCs are characterized by multipotent differentiation abilities in several lineages, fast proliferation, and specific mesenchymal markers. These features, associated with their immunoregulatory properties, through cell-cell contact or secretion of soluble factors , may explain the role played by bone marrow-derived MSC (BM-MSC) in allograft rejection and graft-versus-host disease (GvDH) [3-5]. In addition, BM-MSCs express human leukocyte antigen (HLA) class I molecules that facilitate their escape to natural killer (NK) cells [6, 7]. In fact, the primary function of NK cells is the immunosurveillance and the absence or altered expression of major histocompatibility complex (MHC) class I molecules render target cells susceptible to NK cell attack [8-10]. Despite their HLA class I expression, BM-MSCs are recognized and killed by cytokine-activated NK cells, even if they can also strongly inhibit NK cell cytotoxicity [6, 7, 11]. The complex interaction between NK cells and BM-MSC is not completely understood, but it seems clear that the main mechanism of this interaction is mediated by the activating receptors on NK cells and activating ligands expressed by MSC. In particular, the natural killer group 2D (NKG2D) is not only critically involved in immune surveillance against malignant cells by recognizing stress-inducible MHC class I chain-related protein (MIC)-A and MICB and the UL16-binding proteins (ULBP)1-4 family expressed on tumor cells, but also on NK/MSC interaction [6, 12]. Recently, it has been reported that MSC derived from adult bone marrow also express functional Toll-like receptors (TLR) (in particular TLR-3 and TLR-4), that promote their survival and proinflammatory cytokine secretion [13-18]. TLR are also expressed on fibroblasts, macrophages, dendritic cells, epithelial cells, and lymphocytes. They recognize viral double-stranded RNA (dsRNA), single-stranded RNA (ssRNA), and bacterial products and they can be expressed on the cell surface (TLR1, 2, 4, 5, and 10) or require the internalization of the virus and its replication to release the viral RNA into endosomes (TLR3, 7, 8, and 9) [19, 20]. Beside TLR-3, TLR ligands activate the Myeloid differentiation primary response gene (88) (MyD88) and a complex network of adapter molecules that includes IL-1 receptor-associated kinase and the tumor necrosis factor-receptor-associated factor-6, which leads to the NF-kB nuclear translocation and the consequent inflammatory response. By modulating cell activity, TLRs play a critical role in immune response  and in allograft rejection [22, 23]. MSCs derived from bone marrow, cord blood, adipose tissues, and Wharton's jelly express several TLR that promote their viability, proliferation, and cytokine secretion [13, 15, 16, 24]. In addition, recently Waterman et al.  have demonstrated that TLR triggering polarizes MSC toward an immunosuppressive (MSC2) or a proinflammatory (MSC1) phenotype (TLR3 and TLR4, respectively). Noteworthy, MSC1 (TLR4) supports PBMC activation while unprimed MSC and MSC2 (TLR3) suppress it. Moreover, several papers report diverging effects of TLR on MSC regulatory functions [15, 16, 18, 25], but these different results are probably linked to different culture conditions and experimental procedures. Because MSC, TLR, and NK cells play a critical role in GvDH treatment [5, 22, 26, 27], this study was conducted in order to evaluate the effects of several TLR ligands on MSC/NK interaction. In addition, since TLR ligands apparently modulate sources of MSC other then those derived from bone marrow, we compared the effects of TLR ligands also on human embryonic stem cell lines (H1 and H9)-derived MSC (ES-MSC), which have already been demonstrated to display inhibitory properties against immune cells [28-30]. In conclusion, this study indicates that the proinflammatory environment induced by TLR ligands leads to the modulation of surface expression and secretion of MICA by primed MSC. Moreover, MSCs, behaving like tumor cells, exploit modulation of MICA expression/secretion MICA not only to protect themselves against activated NK cells but also to inhibit NK cytolytic functions.