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 (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.
Rutella
Sergio
S
Department of Hematology, Laboratory of Immunology, Catholic University Medical School, Rome, Italy. sergiorutella@tin.it
Bonanno
Giuseppina
G
Pierelli
Luca
L
Mariotti
Andrea
A
Capoluongo
Ettore
E
Contemi
Anna Maria
AM
Ameglio
Franco
F
Curti
Antonio
A
De Ritis
Daniela G
DG
Voso
Maria Teresa
MT
Perillo
Alessandro
A
Mancuso
Salvatore
S
Scambia
Giovanni
G
Lemoli
Roberto M
RM
Leone
Giuseppe
G
D000328:Adult; D000941:Antigens / Q000187:drug effects; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects; D018929:Cell Culture Techniques; D002454:Cell Differentiation / Q000187:drug effects*; D003713:Dendritic Cells / Q000187:drug effects*; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D006801:Humans; D016898:Interferon-alpha / Q000096:biosynthesis* / Q000187:drug effects; D016753:Interleukin-10 / Q000096:biosynthesis*; D008297:Male; D009000:Monocytes / Q000187:drug effects; D044967:Serum
D000941:Antigens; D016898:Interferon-alpha; D016753:Interleukin-10; D016179:Granulocyte Colony-Stimulating Factor