44,45 GM-CSF requires signal transducer and activator of transcription 5 (STAT5) to suppress Flt-3-driven pDC development.46 STAT5 activation by GM-CSF promptly reduces the expression of essential pDC-related genes in lin− Flt3+ haematopoietic
progenitor cell cultures in the presence of Flt3L.46 By contrast, STAT3 has been shown to be essential for the proliferation of bone marrow progenitors in response to Flt3L,46 and pDC and cDC numbers were shown to be reduced in STAT3-deficient mice. However, STAT3 was not shown to be required for the commitment or development of pDCs, because STAT3-deficient pDCs responded to CpG ODN by producing IFN-α, a characteristic of differentiated pDCs. Taken together, these data reveal a suppressive role for STAT5 and a proliferative role for STAT3 in regulating the production of pDCs. Further to this, studies have demonstrated that buy CCI-779 TLR9 ligation by CpG ODN MI-503 diminished STAT5 activation by IL-7,29 and LPS stimulation led to increased STAT3 activity in human immature monocyte-derived DCs.27 We therefore suggest that the mechanism driving pDC generation at the expense of BMDCs
in response to stimulation with LPS or CpG ODN involves reduced GM-CSF-mediated signalling as a result of decreased STAT5 activity. As Flt3L has been shown to be produced by human bone marrow stromal cells,47 we also suggest that Flt3L is secreted in response to the stimuli and that the signal provided by Flt3L is boosted by increased STAT3 activity.
This hypothesis could be tested by culturing bone marrow cells with GM-CSF in the presence or absence of LPS or CpG ODN and assessing the Flt3L-dependent production and phosphorylation of STAT3 and STAT5, and these experiments are under way. The authors report no conflict of interest. Figure S1. Daily addition of TNF-α does not reverse the effects of LPS or CpG on BMDC production. BALB/c bone marrow cells (5 × 105) were cultured for 6 days with GM-CSF in the presence or absence of LPS or CpG ODN in the presence or absence of daily additions of 20 mg/ml anti-TNF-α for 6 days. Surface markers were analysed by flow cytometry. Results are based on data for 10 000 gated events. Progesterone Data shown are representative of two similar experiments. “
“Chronic graft-versus-host disease (cGVHD) is characterised by a complex etiology of both alloimmune- and autoimmune-mediated disease progression and pathology, and is consequently difficult to control. The therapeutic potential of regulatory T (Treg) cells for cGVHD is currently being investigated; however, the relative ability of Treg cells with defined antigen specificities for auto- and alloantigen to prevent disease has not been previously examined.