TGF-β combined with M-CSF and IL-4 induces generation of immune inhibitory cord blood dendritic cells capable of enhancing cytokine-induced ex vivo expansion of myeloid progenitors

Abstract

Tolerogenic dendritic cells (DCs) may be valuable in transplantation for silencing immune reaction. Macrophage colony-stimulating factor (M-CSF)/IL-4 induces differentiation of cord blood (CB) monocytes into DCs (M-DCs) with tolerogenic phenotype/function. We assessed whether factors produced by tolerogenic DCs could modulate hematopoiesis. TGF-β1 added to CB M-DC cultures induced bona fide DC morphology (TGF-M-DCs), similar to that of DCs generated with TGF-β and granulocyte-macrophage colony-stimulating factor (GM-CSF)/IL-4 (TGF-GM-DCs). Of conditioned media (CM) produced from TGF-M-DCs, TGF-GM-DCs, M-DCs, and GM-DCs, TGF-M-DC CM was the only one that enhanced SCF, Flt3 ligand, and TPO expansion of myeloid progenitor cells ex vivo. This effect was blocked by neutralizing anti–M-CSF Ab, but protein analysis of CM suggested that M-CSF alone was not manifesting enhanced expansion of myeloid progenitors. LPS-stimulated TGF-M-DCs induced T-cell tolerance/anergy as effectively as M-DCs. TGF-M-DCs secreted significantly lower concentrations of progenitor cell inhibitory cytokines and were less potent in activating T cells than TGF-GM-DCs. Functional differences between TGF-M-DCs and TGF-GM-DCs included enhanced responses to LPS-induced ERK, JNK, and P38 activation in TGF-M-DCs and their immune suppressive–skewed cytokine release profiles. TGF-M-DCs appear unique among culture-generated DCs in their capability for silencing immunity while promoting expansion of myeloid progenitors, events that may be of therapeutic value.

Dendritic Cell-Secreted Cytotoxic T-Lymphocyte-Associated Protein-4 Regulates the T-cell Response by Downmodulating Bystander Surface B7

“…2D). Moreover, staining of immature tolerizing or ''tolerogenic'' DC generated in the presence of M-CSF and TGF-b [28] indicated a CD11c…”

A synthetic peptide homologous to IL-10 functional domain induces monocyte differentiation to TGF-β+ tolerogenic dendritic cells

“…Ordinarily, in the absence of infection or inflammatory agents, iDCs capture soluble self-proteins or apoptotic bodies in the periphery and suppress auto-reactive T cells in the lymph nodes, thereby controlling autoimmune responses (Hawiger et al 2001;Steinman et al 2003). Since the transport, processing, and presentation of self-antigens (Ags) for tolerance induction require partial DC maturation mediated by microbial molecules and cytokines , other factors such as IL-10 and TGF-␤ also appear to play important roles in maintaining DCs in an immature-like state mediating tolerogenic responses (Li et al 2007;Steinbrink et al 1997).…”

Robust expansion of dendritic cells in vivo by hydrodynamic FLT3L-FC gene transfer

“…Certain cytokine combinations can drive the generation of DC subsets with specific functional properties: for example, transforming growth factor-beta (TGF-β), M-CSF and IL-4 combine to generate tolerogenic DC from human cord blood monocytes [6,7]. FLT3L used alone generates bone marrow cultured DC that share many features with freshly isolated DC from normal mice, including morphology, surface marker expression, and production of inflammatory mediators in response to stimulation [8].…”