Effects of Liver-Derived Dendritic Cell Progenitors on Th1- and Th2-Like Cytokine Responses In Vitro and In Vivo

Abstract

There is evidence that donor-derived dendritic cells (DC), particularly those at a precursor/immature stage, may play a role in the immune privilege of liver allografts. Underlying mechanisms are poorly understood. We have examined the influence of in vitro generated mouse liver-derived DC progenitors (DCp) on proliferative, cytotoxic, and Th1/Th2 cytokine responses induced in allogeneic T cells. Liver DCp, propagated in GM-CSF from C57B10 mice (H2b), induced only minimal proliferation, and weak cytotoxic responses in allogeneic (C3H; H2k) T cells compared with mature bone marrow (BM)-derived DC. Flow-cytometric analysis of intracellular cytokine staining revealed that mature BM DC, but not liver DCp, elicited CD4+ T cell production of IFN-γ. Intracellular expression of IL-10 was very low in both BM DC- and liver DCp-stimulated CD4+ T cells. Only stimulation by liver DCp was associated with IL-10 secretion in primary MLR. Notably, these liver DCp cocultured with allogeneic T cells stained strongly for IL-10. Following local (s.c.) injection in allogeneic recipients, both BM DC and liver DCp homed to T cell areas of draining lymph nodes and spleen, where they were readily detected by immunohistochemistry up to 2 wk postinjection. Liver DCp induced clusters of IL-10- and IL-4-secreting mononuclear cells, whereas Th2 cytokine-secreting cells were not detected in mice injected with mature BM DC. By contrast, comparatively high numbers of IFN-γ+ cells were induced by BM DC. Modulation of Th2 cytokine production by donor-derived DCp may contribute to the comparative immune privilege of hepatic allografts.

Functional modification of CD11c+ liver dendritic cells during liver regeneration after partial hepatectomy in mice

“…In fact, these potentially "tolerogenic" events (increase in IL-10 and decrease in IFN-␥ gene transcription) occur in primary MLC culture in presence of LDC isolated from partially hepatectomized animals. According to these data, several authors show that immature DC can induce the development of T cell hyporesponsiveness or T regulatory cells that can promote tolerance, [34][35][36] a finding in keeping with the polarization toward Th2 cytokine production by LDC observed in the current study. SDC isolated at the same time as LDC did not show such changes in their IL-10 and IFN-␥ gene transcription or in their ability to modulate cytokine production by naïve T-cells.…”

Immune Modulation by Silencing IL-12 Production in Dendritic Cells Using Small Interfering RNA

“…Another possible explanation for suppressed MLR in siRNA-IL12p35-transfected DC is that the increased IL-10 production may act as an inhibitor of T cell proliferation (37,38). Other studies examining naturally occurring Th2-promoting DC have shown that these cells have a reduced allostimulatory function and reduced IL-12 production (39,40). The combination of Th2-promoting properties as well as poor allostimulation suggests that siRNA-IL12p35-transfected DC may possess the phenotype of a "tolerogenic" DC and thus may be useful for treatment of Th1-mediated autoimmune diseases and transplant rejection.…”

Administration of an Antigen at a High Dose Generates Regulatory CD4+ T Cells Expressing CD95 Ligand and Secreting IL-4 in the Liver

“…First, these regulatory T cells may be generated in situ in the liver by antigenic activation by hepatic APC. In fact, hepatic sinusoidal endothelial cells and dendritic cells can present Ags (3,4,35). Alternatively, these regulatory T cells can develop in GALT (14) and then migrate to the liver.…”