TLR Ligands Stimulation Protects MSC from NK Killing

Abstract

Mesenchymal stem cells (MSCs) play a fundamental role in allograft rejection and graft-versushost disease through their immunosuppressive abilities. Recently, Toll-like receptors (TLR) have been shown to modulate MSC functions. The aim of this study was to investigate the effects of several TLR ligands on the interaction between MSC and natural killer (NK) cells. Our results show that TLR-primed adult bone marrow and embryonic MSC are more resistant than unprimed MSC to IL-2-activated NK-induced killing. Such protection can be explained by the modulation of Natural Killer group 2D ligands major histocompatibility complex class I chain A and ULBP3 and DNAM-1 ligands by TLR-primed MSC. These results indicate that MSCs are able to adapt their immuno-behavior in an inflammatory context, decreasing their susceptibility to NK killing. In addition, TLR3 but not TLR4-primed MSC enhance their suppressive functions against NK cells. However, the efficiency of this response is heterogeneous, even if the phenotypes of different analyzed MSC are rather homogeneous. The consequences could be important in MSC-mediated cell therapy, since the heterogeneity of adult MSC responders may be explored in order to select the more efficient responders. STEM CELLS 2014;32:290-300

Controversial Role of Toll-like Receptor 4 in Adult Stem Cells

“…Similar pro-proliferative effects have been observed after stimulation of adult human bone marrow MSCs with 1 μg/ml LPS from E. coli (O55:B5) for 48 h [72]. Besides bone marrow MSCs, LPS may also have proliferation inducing effect in peripheral MSCs isolated from human turbinate tissue [18].…”

“…Apparently, TLR agonists have little effects on the immunogenicity state [77]. A recent study indicates that TLR4-primed MSCs are more resistant to NK-induced killing [72]. In mixed lymphocyte reactions, MSC can induce a significant inhibition of lymphocyte proliferation, while promoting the generation of regulatory T cells (Tregs).…”

Evaluation of gene delivery strategies to efficiently overexpress functional HLA-G on human bone marrow stromal cells

“…37 Some studies indicate that TLR3 and TLR4 activation reduce the inhibitory activity of human BM-MSCs on T-cell proliferation and induce the secretion of proinflammatory molecules capable of promoting the recruitment of inflammatory immune cells, 36,38,39 whereas others report that TLR3 and/or TLR4 engagement enhances the immuno-suppressive properties of human BM-MSCs. 39,40 …”

Mesenchymal stromal cells for treatment of the acute respiratory distress syndrome: The beginning of the story

“…115 Moreover, the priming of bone marrow-derived MSCs with TLR3 and not TLR4 afforded the cells with increased resistance to NK cell killing as well as amplifying their immunosuppressive effects on these cells. 116 Ongoing research in MSC therapy is crucial to uncover how the biological effects of MSCs can be potentiated to enable transition of MSCs to the bedside as the optimal treatment for patients with ARDS.…”