Interaction between Human NK Cells and Bone Marrow Stromal Cells Induces NK Cell Triggering: Role of NKp30 and NKG2D Receptors

Abstract

In this study we have analyzed the interaction between in vitro cultured bone marrow stromal cells (BMSC) and NK cells. Ex vivo-isolated NK cells neoexpressed the activation Ag CD69 and released IFN-γ and TNF-α upon binding with BMSC. Production of these proinflammatory cytokines was dependent on ligation of ICAM1 expressed on BMSC and its receptor LFA1 on NK cells. Furthermore, the NKp30, among natural cytotoxicity receptors, appeared to be primarily involved in triggering NK cells upon interaction with BMSC. Unexpectedly, autologous IL-2-activated NK cells killed BMSC. Again, LFA1/ICAM1 interaction plays a key role in NK/BMSC interaction; this interaction is followed by a strong intracellular calcium increase in NK cells. More importantly, NKG2D/MHC-I-related stress-inducible molecule A and/or NKG2D/UL-16 binding protein 3 engagement is responsible for the delivery of a lethal hit. It appears that HLA-I molecules do not protect BMSC from NK cell-mediated injury. Thus, NK cells, activated upon binding with BMSC, may regulate BMSC survival.

Immunoregulatory function of mesenchymal stem cells

“…Consistent with the low level of surface expression of HLA class I molecules, MSC were highly susceptible to lysis by IL-2-activated NK cells; this was true for both autologous and allogeneic MSC [58][59][60]. The activating NK cell receptors NKp30, NKG2D and DNAM-1 played a major role in the NK cell-mediated cytotoxicity against MSC, which in turn expressed (known) ligands recognized by these receptors, including ULBP, PVR and nectin-2 [61].…”

“…Interaction between ICAM-1 on the latter cells and LFA-1 on NK cells was instrumental for cytokine production to take place. In addition, the NKp30 natural cytotoxicity receptor was found to be involved in NK cell triggering of cytolytic activity or cytokine production upon binding to MSC [59,60].…”

The roles of immune cells in bone healing; what we know, do not know and future perspectives

“…Additionally, within a chronic inflammatory milieu, monocytes have a higher potential to differentiate into osteoclasts through TNF-a dependent mechanism [109]. Excessively activated NK cells could mediate cytotoxicity against allogeneic or autologous MSCs [62,[110][111][112][113]. Both Activated T-lymphocytes and Blymphocytes are well known to release RANKL, which boosts osteoclast differentiation from their progenitors and subsequently provoke the bone lysis [94,114].…”

“…Furthermore, the in vitro studies indicate complicated interactions between NK cells and MSCs, i.e. NK cells functions can be suppressed by MSCs and NK cells can participate in MSC licensing, but also can kill MSCs [62,63,[110][111][112][113]. Thus, further research is necessary to understand the biological importance of these interactions NK cells during physiological fracture healing and how this would affect the cell therapy.…”

“…For autologous MSCs, in vitro studies have shown that NK cells can lyse autologous MSCs similar to allogeneic MSCs [142]. The NK-cell mediated killing of autologous MSCs is related to the low expression of HLA-I molecules and high expression of NK cell activating ligands on the MSC surface [62,[110][111][112][113]. Thus, it is remaining to investigate if under certain conditions, this mechanism could threaten the fate of the transplanted MSCs for fracture healing.…”