Granulocyte colony-stimulating factor promotes the generation of regulatory DC through induction of IL-10 and IFN-alpha

We have recently demonstrated that G-CSF promotes the generation of human T regulatory (TREG) type 1 cells. In this study, we investigated whether the immunomodulatory effects of G-CSF might be mediated by DC. CD14+ monocytes were cultured with serum collected after clinical administration of G-CSF (post-G), which contained high amounts of IL-10 and IFN- § . Similar to incompletely matured DC, monocytes nurtured with post-G serum acquired a DC-like morphology, expressed high levels of costimulatory molecules and HLA-DR, and exhibited diminished IL-12p70 release and poor allostimulatory capacity. Importantly, post- G DC-like cells were insensitive to maturation stimuli. As shown by neutralization studies, IFN- § and, even more pronounced, IL-10 contained in post-G serum inhibited IL-12p70 release by post-G DC-like cells. Furthermore, phenotypic and functional features of post-G DC-like cells were replicated by culturing post-G monocytes with exogenous IL-10 and IFN- § . Post-G DC-like cells promoted Ag-specific hyporesponsiveness in naive allogeneic CD4+ T cells and orchestrated a TREG response that was dependent on secreted TGF- g 1 and IL-10. Finally, neutralization of IL-10 and IFN- § contained in post-G serum translated into abrogation of the regulatory features of post-G DC-like cells. This novel mechanism of immune regulation effected by G-CSF might be therapeutically exploited for tolerance induction in autoimmune disorders.