Treatment With Granulocyte Colony−Stimulating Factor Prevents Diabetes in NOD Mice by Recruiting Plasmacytoid Dendritic Cells and Functional CD4+CD25+ Regulatory T-Cells

Treatment With Granulocyte Colony−Stimulating Factor Prevents Diabetes in NOD Mice by Recruiting Plasmacytoid Dendritic Cells and Functional CD4 + CD25 + Regulatory T-Cells Hassen Kared 1 , Annie Masson 1 , Homa Adle-Biassette 2 , Jean-François Bach 1 , Lucienne Chatenoud 1 and Flora Zavala 1 1 National Institute of Health and Medical Research, INSERM U580, Necker Enfants Malades Research Institute, Hôpital Necker, Paris, France 2 Pathology Laboratory, Bichat-Claude Bernard Hospital, Assistance Publique Hôpitaux de Paris, Paris, France Address correspondence and reprint requests to Flora Zavala, DSc, INSERM U580, Necker Institute, 161 rue de Sèvres, 75743 Paris Cedex 15, France. E-mail: zavala{at}necker.fr Abstract Accumulating evidence that granulocyte colony−stimulating factor (G-CSF), the key hematopoietic growth factor of the myeloid lineage, not only represents a major component of the endogenous response to infections, but also affects adaptive immune responses, prompted us to investigate the therapeutic potential of G-CSF in autoimmune type 1 diabetes. Treatment with G-CSF protected NOD mice from developing spontaneous diabetes. G-CSF triggered marked recruitment of dendritic cells (DCs), particularly immature CD11c lo B220 + plasmacytoid DCs, with reduced costimulatory signal expression and higher interferon-α but lower interleukin-12p70 release capacity than DCs in excipient-treated mice. G-CSF recipients further displayed accumulation of functional CD4 + CD25 + regulatory T-cells that produce transforming growth factor-β1 (TGF-β1) and actively suppressed diabetes transfer by diabetogenic effector cells in secondary NOD-SCID recipients. G-CSF’s ability to promote key tolerogenic interactions between DCs and regulatory T-cells was demonstrated by enhanced recruitment of TGF-β1−expressing CD4 + CD25 + cells after adoptive transfer of DCs isolated from G-CSF− relative to vehicle-treated mice into naive NOD recipients. The present results suggest that G-CSF, a promoter of tolerogenic DCs, may be evaluated for the treatment of human type 1 diabetes, possibly in association with direct inhibitors of T-cell activation. They also provide a rationale for a protective role of the endogenous G-CSF produced during infections in early diabetes. APC, antigen-presenting cell DC, dendritic cell EAE, experimental autoimmune encephalomyelitis FACS, fluorescence-activated cell sorter FITC, fluorescein isothiocyanate G-CSF, granulocyte colony−stimulating factor GVHD,