IFNg-Mediated MHC-II Expression in Mesenchymal Stem Cells (MSC) Is Concentration-Dependent.

A significant concern in tissue repair is allo-rejection in a host with MHC-II mismatch. Since MSC appear to have veto properties to offset its own rejection, these stem cells may serve as ideal candidates in repair medicine. Interferon-g (IFN-g), which exacerbates immune responses, is known to enhance the expression of MHC-II in antigen presenting cells (e.g., macrophages). This led to the question on the mechanism by which MSC act as immune suppressor cells. We hypothesize that endogenous IFN-γ maintains basal MHC-II expression, while increased levels lead to its down regulation. Indeed, we observed a biphasic response of IFN-γ on the expression of MHC-II. While unstimulated MSC produced 19±5 pg/ml IFN-γ, exogenous IFN-γ (>100 U/ml) led to decreased expression of MHC-II. Suppression of IFN-g by siRNA resulted in undetectable MHC-II. The response of exogenous IFN-γ could not be explained by altered expression of IFN-g receptor type I (IFN-γRI) or changes in STAT-1 activation. However, western blots showed multiple isotypes of the MHC-II master regulator transcription factor, CIITA, in IFN-γ-stimulated MSC, with predominance of CIITA exhibiting low efficiency binding to DNA. This observation might explain why MHC-II is undetectable in the presence of high levels of IFN-γ. These findings support a potential for MSC as an adult stem cell in tissue repair.