Human blood CD1c dendritic cells stimulate IL-12-independent IFN-γ responses and have a strikingly low inflammatory profile

Abstract

Adaptive immune responses are initiated by resident myeloid tissue DC. A major fraction of tissue DC express CD1c and is thought to be derived from blood CD1c DC, an idea supported here by the observation that they express tissue-homing molecules and rapidly differentiate into cells with a tissue DC phenotype. Responses are thought to be augmented/modulated further by inflammatory moDC. Although much accepted human myeloid DC cell biology is based on moDC studies, we find these 2 DC populations to be functionally distinct. Stimulated moDC produce high levels of IL-10 and the Th1-promoting cytokine IL-12. Under identical conditions, CD1c DC synthesized no IL-10 and no or low levels of IL-12. Despite this, CD1c DC stimulated a strong Th1 response, demonstrated by IL-12 neutralization to be IL-12 independent, whereas the response induced by moDC was IL-12 dependent. This finding was supported by studies on a patient with a highly reduced ability to synthesize IL-12, whose CD1c DC induced a good Th1 response contrasting with the failure of his moDC, which were impaired in IL-12 production, to induce IFN--secreting T cells. The IL-10 and IL-12 data were confirmed by microarray analysis, which also showed that stimulated moDC produced inflammatory-associated chemokines and cytokines, whereas stimulated CD1c DC showed minimal up-regulation of these genes. Thus, moDC, widely used as a human myeloid DC model, do not faithfully reflect the properties of CD1c tissue DC, making the initial response to a pathogen or vaccine.

Retinoic acid-primed human dendritic cells inhibit Th9 cells and induce Th1/Th17 cell differentiation

“…Interestingly, we observed that these gut-homing CD4 + T cells, generated in the presence of RA-MoDCs, expressed augmented levels of IFN-g in an IL-12-independent manner. Recently, human DCs have been shown to induce IL-12-independent IFN-g [42]. Furthermore, there are reports where RA acts through cell-cell interaction (costimulatory pathways) to modulate IFN-g production [43,44].…”

The Notch Ligand DLL4 Defines a Capability of Human Dendritic Cells in Regulating Th1 and Th17 Differentiation

“…DCs also produce effector-polarizing cytokines that are crucial in directing effective T cell differentiation. (4–8) However, emerging evidence indicates that DCs can drive effector differentiation independent of cytokines. (9, 10) Our studies and others suggest that Notch ligands expressed on the surface of DCs are important in promoting the generation of different lineages of effector T cells.…”

CMRF-56+blood dendritic cells loaded with mRNA induce effective antigen-specific cytotoxic T-lymphocyte responses

“…The hCMRF-56 selection of BDC is clinically feasible and compatible with outpatient and hospital scheduling; nevertheless, further improvements in its efficacy are possible. It is likely, given the low inflammatory profile of mDC (including CD1c C DC, 49 the major fraction of hCMRF-56 BDC), that improved stimulation of BDC (e.g. by CD40 ligation) might increase their migration or their T-cell priming potency.…”