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IFNGamma Priming Protects Fetal and Embryonic MSC from NK Cell-Mediated Killing and Improves their Immunosuppressive Properties: Role of Activating and Inhibitory Receptors

Giuliani M, Poggi A, Bennaceur Griscelli A and Lataillade JJ

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.