IL-4 and CD40 ligation affect differently the differentiation, maturation, and function of human CD34+ cell-derived CD1a+CD14− and CD1a−CD14+ dendritic cell precursors in vitro

Abstract

Abstract:We examined the effect of interleukin (IL)-4 or CD40 ligation on the differentiation and maturation of CD1a ؉ CD14 ؊ and CD1a ؊ CD14 ؉ dendritic cell (DC) precursors. Cord blood CD34 ؉ cells were cultured with granulocyte-macrophage colony-stimulating factor (GM-CSF) and tumor necrosis factor ␣ (TNF-␣), to which stem cell factor and Flt-3 ligand were added for 5 days. Phenotypic analysis of DC precursors on culture day 7 showed that CD1a ؉ CD14 ؊ cells expressed higher CD11c and CD80 levels and lower CD116/GM-CSFR and CCR-5 levels than their CD1a ؊ CD14 ؉ counterparts. Culturing CD1a ؉ CD14 ؊ precursors with GM-CSF and TNF-␣ resulted in DC with heterogeneous CD1a, HLA;SMDR (DR), CD11b, and CD83 expression, 10% of which acquired CD14. IL-4 and CD40 ligation affected their differentiation in contrasting ways: IL-4 induced CD1a hi CD14 ؊ DR lo CD11b ؉ CD83 ؊ S100 ؉ DC with reduced MLRstimulating capacity, whereas CD40 ligation led to CD1a lo/-CD14 ؊ CD40 ؊ DR hi CD11b ؊ CD83 ؉ S100 ؉/-DC with stronger MLR-stimulating capacity. Also, both IL-4 and CD40 ligation promoted RelB expression and nuclear translocation. When CD1a ؊ CD14 ؉ precursors were maintained in only the presence of GM-CSF and TNF-␣, this led to mixed populations of adherent macrophages and nonadherent CD1a ؊ CD14 ؉ monocytes, and of CD1a ؉ CD14 ؊ and CD1a ؉ CD14 ؉ DC, which were DR lo CD11b ؉ -CD83 ؊ S100 ؊ . IL-4 or CD40 ligation prevented their differentiation into macrophages and resulted in DC with phenotypes close to those issued from CD1a ؉ CD14 ؊ precursors, with only a minority staying CD14 ؉ but most being S100 ؊ ; their MLRstimulating capacity also increased but remained lower than that of DC differentiated from CD1a ؉ CD14 ؊ precursors. Thus, IL-4 or CD40 ligation induced CD1a ؉ CD14 ؊ and CD1a ؊ CD14 ؉ DC precursors to differentiate into phenotypically close but functionally different DC populations, suggesting that DC function is primarily determined by their origin. The heterogeneity of DC should then be related to different developmental pathways and to different stages of maturation/activation. J. Leukoc. Biol. 64: 235-244; 1998.

IL-4 Confers NK Stimulatory Capacity to Murine Dendritic Cells: A Signaling Pathway Involving KARAP/DAP12-Triggering Receptor Expressed on Myeloid Cell 2 Molecules

“…IL-4 has been reported to induce the loss of macrophage features, increase MHC expression, up-regulate costimulatory and DC-SIGN molecules, enhance Ag uptake and processing, and synergize with other factors to increase IL-12 production (39 -43). However, when added to DC precursors differentiated from CD34 ϩ progenitors, IL-4 delays maturation of Langerhans cells and reduces the allostimulatory function of DC (44,45). We confirmed these findings and showed that mouse BM-DC GM/IL4 behave like BM-DC GM in the sense that they acquired a fully mature phenotype only after LPS stimulation (M. Terme, data not shown).…”

Activation through Cannabinoid Receptors 1 and 2 on Dendritic Cells Triggers NF-κB-Dependent Apoptosis: Novel Role for Endogenous and Exogenous Cannabinoids in Immunoregulation

“…It is not known whether the DCs generated using different cytokines would exhibit differential sensitivity to THC-induced apoptosis. Cytokines such as IL-4 and TNF-␣ have been shown to activate NF-B (51,52) and inasmuch as we demonstrated that THC-induced activation of NF-B regulates apoptosis in DCs, it would be interesting to further investigate the effect THC on DCs generated using GM-CSF and IL-4 or TNF-␣. Such reports also suggest that our studies may have limitations in extrapolating the results to human DCs.…”

Tumor Necrosis Factor Alpha‐Stimulated Endothelium: An Inducer of Dendritic Cell Development from Hematopoietic Progenitors and Myeloid Leukemic Cells

“…However, this only induced the generation of granulocytes and not DC. Similarly, IL-4 also did not lead to DC differentiation, though it is known to suppress the development of monocytes [37] and to increase VCAM-1-dependent T-lymphocyte transmigration [38]. Thus, although these two cytokines are known to increase the expression of endothelial cytokines and several surface molecules [39,40], neither were able to promote the differentiation of CD34 + cells into DC.…”