IL-1 and IFN-gamma differentially program human dendritic cells exposed to beta-glucan via IkappaB-zeta regulation (P6279)

Abstract

Abstract The molecular networks controlling the DC programming in response to C-type lectin receptor agonists including beta-glucan, a fungal and bacterial component and ligand for the Dectin-1 receptor, are still poorly characterized. We studied these immunological aspects by comparing the response of human mono-DCs to the Dectin-1 ligand, beta-glucan, and to the TLR4 ligand, LPS using a gene expression/perturbation approach. Gene expression analysis of mono-DCs stimulated by beta-glucan identified IL-1, TNF, and type I IFN encoded by “early/immediate” type genes as predicted regulators of the beta-glucan-induced “late” transcriptional response. A perturbation analysis revealed that endogenous IL-1, via the nuclear factor IkappaB-zeta, selectively promoted the expression of beta-glucan-induced “late” genes such as those encoding IL-6 and IL-23, thus programming DCs to initiate Th17 responses. TNF and type I IFN were found to modulate the response to both beta-glucan and LPS. IFN-gamma counteracted the activity of IL-1 and reprogrammed human mono-DCs to promote Th1-like cells rather than Th17 in response to beta-glucan. Our data provide evidence that IL-1 and IFN-gamma promote distinct adaptive immune responses against the fungal and bacterial component beta-glucan by differentially modulating the DC programming. They also suggest potential strategies to modulate the immunity against beta-glucan containing pathogens.