Abstract
G-CSF is a modulator of T-cell and DC functions. Previous reports show that monocytes from G-CSF-treated (post-G) healthy donors differentiate into tolerogenic DC in vitro in the presence of autologous serum, containing high levels of IL-10 and IFN-α, and in turn induce type 1 Treg (Tr1) cells. However, the direct effect of G-CSF on DC differentiation was not investigated. Here, we show that monocytes differentiated in the presence of exogenous G-CSF (G-DC) remain CD14+CD1a−, but acquire a DC-like morphology, express CD83 and CD86 and low levels of the tolerogenic markers Ig-like transcript (ILT)4 and HLA-G. G-DC spontaneously produce IL-10 and, upon stimulation, low levels of IL-12. G-DC display low stimulatory capacity and induce anergy in naïve T cells, but do not confer suppressive function. Therefore, in vitro differentiation of monocyte-derived DC in the presence of G-CSF can replicate some but not all features of post-G DC. These findings indicate that the tolerogenic properties of G-CSF do not exclusively reside in its direct effect on DC, which in turn induce T-cell anergy, but also in its ability to generate a tolerogenic milieu in vivo, which is necessary for Tr1 cell induction and cannot be replicated in vitro.
Highlights
G-CSF was initially identified as a growth factor for neutrophils [1]
G-DC were differentiated from peripheral blood monocytes in the presence of G-CSF and IL-4 and compared to immature DC differentiated with GM-CSF and IL-4 for 7 days, which in some cases were exposed to LPS during the last 2 days of culture to obtain mature DC
G-DC were differentiated in the absence of GM-CSF since it masked the effects of G-CSF in terms of phenotype and cytokine production [36]
Summary
G-CSF was initially identified as a growth factor for neutrophils [1]. Inflammatory stimuli can induce G-CSF production from bone marrow stromal cells, endothelial cells, macrophages and fibroblasts. The G-CSF receptor (G-CSFR, CD114) is expressed on early myeloid progenitors, mature granulocytes, monocytes/ macrophages [1], endothelial cells and other non-hematopoietic tissues [2], and on human T and B cells [3,4,5]. The proliferation of T cells from G-CSF-treated patients [9] and healthy stem cell donors [18, 19] is profoundly reduced, due to a G1 arrest in T-cell cycle [20, 21]. This modulation might be indirectly mediated by down-regulation of co-stimulatory
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