Abstract
Dendritic cell (DC)-based immunotherapy makes use of the DC’s ability to direct the adaptive immune response toward activation or inhibition. DCs perform this immune orchestration in part by secretion of selected cytokines. The most potent anti-inflammatory cytokine interleukin-10 (IL-10) is under tight regulation, as it needs to be predominantly expressed during the resolution phase of the immune response. Currently it is not clear whether there is active suppression of IL-10 by DCs at the initial pro-inflammatory stage of the immune response. Previously, knockdown of the DC-specific transcription factor DC-SCRIPT has been demonstrated to mediate an extensive increase in IL-10 production upon encounter with pro-inflammatory immune stimuli. Here, we explored how DC-SCRIPT contributes to IL-10 suppression under pro-inflammatory conditions by applying chromatin immunoprecipitation sequencing analysis of DC-SCRIPT and the epigenetic marks H3K4me3 and H3K27ac in human DCs. The data showed binding of DC-SCRIPT to a GA-rich motif at H3K27ac-marked genomic enhancers that associated with genes encoding MAPK dual-specificity phosphatases (DUSPs). Functional studies revealed that upon knockdown of DC-SCRIPT, human DCs express much less DUSP4 and exhibit increased phosphorylation of the three major MAPKs (ERK, JNK, and p38). Enhanced ERK signaling in DC-SCRIPT-knockdown-DCs led to higher production of IL-10, which was reverted by rescuing DUSP4 expression. Finally, DC-SCRIPT-knockdown-DCs induced less IFN-γ and increased IL-10 production in naïve T cells, indicative for a more anti-inflammatory phenotype. In conclusion, we have delineated a new mechanism by which DC-SCRIPT allows DCs to limit IL-10 production under inflammatory conditions and potentiate pro-inflammatory Th1 responses. These insights may be exploited to improve DC-based immunotherapies.
Highlights
Immunotherapy has gained great success in recent years due to the success of checkpoint inhibitors targeting the PD-1/PD-L1 or CTLA-4 pathways [1,2,3,4]
Dendritic cells are the sentinels of the immune system, playing a decisive role in the balance between immunogenic and tolerogenic immune responses [10], the molecular mechanism of how DCs control production of the anti-inflammatory cytokine IL-10 in an inflammatory setting is still unclear
We show that DC-SCRIPT, a DC-specific transcription factor in the immune system, binds to GA-rich sequences in enhancerand promoter-associated DNA regions for many immune-related genes, including an enhancer for the MAPK phosphatase DUSP4
Summary
Immunotherapy has gained great success in recent years due to the success of checkpoint inhibitors targeting the PD-1/PD-L1 or CTLA-4 pathways [1,2,3,4]. These checkpoint inhibitors act on T cells, and it is widely accepted that T cells are quintessential in the fight against cancer. T cells are not capable of eliciting an anti-tumor response by themselves, because without the right instructions, the T cells will remain naïve or become tolerogenic [5]. Information regarding intracellular regulatory circuits in DCs is far scarcer, and could possess potential for future therapeutic strategies as well
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