Granulocyte Colony-Stimulating Factor Promotes the Generation of Regulatory DC Through Induction of IL-10 and IFN-alpha

Eur J Immunol. 2004 May;34(5):1291-302. doi: 10.1002/eji.200324651.

Abstract

We have recently demonstrated that G-CSF promotes the generation of human T regulatory (T(REG)) 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-alpha. 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-alpha 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-alpha. Post-G DC-like cells promoted Ag-specific hyporesponsiveness in naive allogeneic CD4(+) T cells and orchestrated a T(REG) response that was dependent on secreted TGF-beta 1 and IL-10. Finally, neutralization of IL-10 and IFN-alpha 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antigens / drug effects
  • CD4-Positive T-Lymphocytes / drug effects
  • Cell Culture Techniques
  • Cell Differentiation / drug effects*
  • Dendritic Cells / drug effects*
  • Female
  • Granulocyte Colony-Stimulating Factor / pharmacology*
  • Humans
  • Interferon-alpha / biosynthesis*
  • Interferon-alpha / drug effects
  • Interleukin-10 / biosynthesis*
  • Male
  • Monocytes / drug effects
  • Serum

Substances

  • Antigens
  • Interferon-alpha
  • Interleukin-10
  • Granulocyte Colony-Stimulating Factor