Monocytic suppressor cells derived from human peripheral blood suppress xenogenic immune reactions

Background: Myeloid-derived suppressor cells (MDSC) were initially found to contribute to the immunosuppression in tumor patients and have recently been recognized as a subset of innate immune cells that are capable of regulating adaptive immunity. A variety of innate immune stimul I such as Lipopolysaccharide (LPS), which act as a double-edged sword, induce both the maturation of dendritic cells (DC) and the expansion of MDSCs. Methods: In this study, we isolated MDSCs from peripheral blood mononuclear cells and examined the suppressive effect of MDSCs against cytotoxic T lymphocyte (CTL)-mediated xenocytotoxicity. Results: Peripheral blood monocytes cultured in the presence of GMCSF and IL-4 were stimulated with polyiosinic-polycytidylic acid [poly (I:C)] or LPS. Flow cytometric analyses revealed that LPS and poly I:C stimulation allows the CD33(+) CD14(+) HLA-DR- subset to be significantly increased. To assess the suppressive capacity of MDSCs in xenotoxicity, CTL assay was performed. Poly (I:C)-activated MDSCs dramatically suppressed the CTL xenocytotoxicity. Phagocytosis assays revealed that activated MDSCs aggressively phagocytose the xenogenic CTLs. Characterization of MDSCs by real-time PCR revealed that poly (I:C) and LPS-stimulated MDSCs expressed significant amounts of mRNA for indolamine 2,3-dioxygenase (IDO) compared to untreated MDSCs. Furthermore, when MDSCs were incubated with the IDO inhibitor, the MDSC-induced suppression of xenocytotoxicity was abolished. Taken together, the possibility that activated MDSCs could induce apoptosis in xenogenic CTLs via an IDO-dependent manner and aggressively phagocytose apoptotic CTLs cannot be excluded. Conclusion: These findings indicate that MDSCs have a great deal of potential as a therapeutic strategy for dealing with xenograft rejection. Further investigations of the underlying mechanisms will facilitate the development of this therapeutic strategy.