Abstract
The enhancement of Mesenchymal Stem Cells (MSC) immunosuppressing function can favour the engraftment of MSC employed in tissue repair. IFN-γ is a pro-inflammatory cytokine, which induces tolerogenic molecules in bone marrow (BM) MSC. We have investigated the interaction of IFN-γ primed MSC from fetal (FL-MSC) and embryonic (ES-MSC) origin with natural killer (NK) cells. IFN-γ -primed FL-/ES-MSC were less susceptible to NK cell-mediated killing, where a major role was played by the IFN-γ-induced up-regulation of HLA-ABC and HLA-E. Monoclonal antibody-mediated blocking of CD94/NKG2A on NK cells increased killing of IFN-γ-primed MSC, suggesting a role of this NK cell inhibitory receptor in MSC protection. NKG2D ligands (such as MICA), LFA-1 and ICAM1 expressed on MSC were also involved in NK cell-mediated killing of un-primed, but not of IFN-γ-primed, FL-/ES-MSC. Importantly, NK cells from IFN-γ-primed FL-/ES-MSC-NK cell co-cultures displayed a reduced intracellular free calcium increase, pERK activation, degranulation, cytolysis and IFN-γ production upon interaction with the NK sensitive target cell K562 compared to NK cells from un-primed FL/ES-MSC-NK cell co-cultures. Finally, PGE-2, increased during NK/MSC co-cultures, appeared to be a key soluble factor responsible for FL-/ES-MSC-mediated immunosuppressive effect. These results suggest that surface molecules such as MICA, HLA-E and ICAM1 can play a role in recognizing un-primed FL/ES-MSC but not IFN-γ-primed MSC where HLA-I is a key molecule for NK cellmediated recognition. Further, the strong immunosuppressive effect of IFN-γ-primed FL-/ES-MSC on NK cells could be exploited in cellular therapy protocols.
Highlights
Natural killer (NK) cells are characterized for their ability to kill transformed or malignant cells without prior activation [1,2]
To determine the reason why IFNγ primed FL/ES-Mesenchymal Stem Cells (MSC) were less susceptible to NK cell-mediated lysis, we first evaluated the expression of HLA-I molecules, which role has been shown in MSC protection from NK cells [14] in FL/ES-MSC upon incubation with IFNγ
Given that IFNγ increased the expression of HLA-I, HLA-E and B7H1 on MSC, we explored if these molecules were involved in MSC protection to NK lysis (Figure 3a)
Summary
Natural killer (NK) cells are characterized for their ability to kill transformed or malignant cells without prior activation [1,2] They are involved in immune responses against viral pathogens, but they play a critical role in organ transplantation and GvHD treatment [3,4]. IFN gamma (IFN-γ) is a classical Th1 pro-inflammatory cytokine largely secreted during infection or inflammatory response, and it is known to induce tolerogenic molecules (such as IDO, B7-H1 and HLA-G)in licensed (primed)human MSC [16,17,19,23,40,41,42,43,44,45].By consequence, IFN-γ primed MSC better inhibit T cell proliferation and increase their HLA class I expression that plays a critical role in protecting adult from NK killing [10,14].a beneficial effect of IFN-γ on MSC activity is found in vitro and in
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