STAT3 and IL-10 inhibit interferon signaling in type 1 conventional dendritic cells

Abstract Conventional dendritic cells (cDCs) are the primary antigen presenting cells of the immune system, and thus control adaptive immunity. Type 1 cDCs (cDC1s) are crucial for mounting protective T cell responses against tumors and viruses. Recently, we reported that interleukin (IL)-10 inhibits polyinosinic-polycytidylic acid (poly I:C; a toll-like receptor 3 agonist) induced maturation of cDC1s in a signal transducer and activator of transcription (STAT) 3-dependent manner. In addition, using a tumor vaccine approach, we demonstrated that STAT3-deficient (Stat3Δ/Δ) cDC1s are more capable of inducing anti-tumor immunity than STAT3-sufficient (Stat3fl/fl) cDC1s. To further investigate how STAT3 and IL-10 inhibit cDC1 function, we performed RNA-sequencing using Stat3Δ/Δ and Stat3fl/fl cDC1s treated with IL-10, poly I:C, or both IL-10 and poly I:C. Gene Set Enrichment Analysis revealed that although many inflammatory signaling pathways are enriched in cDC1s upon treatment with poly I:C, only the interferon-alpha (IFN-α) response pathway is inhibited by IL-10 and STAT3. Furthermore, Ingenuity Pathway Analysis identified IFNs, and components of IFN receptor signaling, such as STAT1, as the primary targets of IL-10/STAT3-mediated inhibition. Therefore, pathway analyses suggest IL-10 and STAT3 inhibit poly I:C-induced IFN signaling in cDC1s. Indeed, IL-10 was found to inhibit poly I:C-induced accumulation of phosphorylated STAT1 by immunoblot. Moreover, investigations into specific IFNs determined that IFN-β and IFN-γ, but not IFN-λ, induce IFN-stimulated genes in cDC1s. Currently, studies are underway to further dissect the role of IFNs in cDC1 function and IL-10/STAT3-mediated inhibition of poly I:C-induced maturation.