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Dendritic cell (DC) activation and cytokine production is tightly regulated. In this study, we found that Zbtb10 expression is activation dependent and it is essential for the immunogenic function of cDC1. Zbtb10 knockdown (KD) significantly reduced the expression of co‐stimulatory genes CD80 and CD86 along with cytokines including IL‐12, IL‐6, and IL‐10, in activated cDC1 Mutu‐DC line. Consequently, the clonal expansion of CD44+ effector T cells in co‐cultured CD4+ T cells was drastically reduced owing to significantly reduced IL‐2. At the same time, these CD44+ effector T cells were unable to differentiate toward Tbet+IFNγ+ Th1 subtype. Instead, an increased frequency of Th2 cells expressing GATA3+ and IL‐13+ was observed. Interestingly, in Zbtb10 KD condition the co‐cultured T cells depicted increased expression of PD1 and LAG3, the T‐cell anergic markers. Moreover, the global transcriptome analysis identified that Zbtb10 is pertinent for DC activation and its depletion in cDC1 completely shuts down their immune responses. Mechanistic analysis revealed that Zbtb10 KD enhanced the expression of NKRF (NF‐κB repressing factor) leading to drastic suppression of NF‐κB related genes. Zbtb10 KD abrogated p65 and RelB nuclear translocation, thereby controlling the activation and maturation of cDC1 and the ensuing adaptive T cell responses. [ABSTRACT FROM AUTHOR]

Plasmacytoid dendritic cells (DCs) are reported to induce robust type‐I interferon (IFN) response, whereas cDC1 DCs develop moderate type‐I IFN response upon TLR9 stimulation. It is very interesting to understand how this signaling under TLR9 is tightly regulated for the induction of type‐I IFNs. Here, we report co‐repressor protein NCoR1 as the major factor fine‐tuning the signaling pathways regulating IFN‐β expression under TLR9 in cDC1 DCs. We found that NCoR1 knockdown induced a robust IFN‐β‐mediated antiviral response upon TLR9 activation in cDC1 DCs. At the molecular level, we showed that NCoR1 directly repressed MyD88‐IRF7 signaling axis in cDC1 cells. Therefore, NCoR1 depletion enhanced pIRF7 levels, IFN‐β secretion, and downstream pSTAT1‐pSTAT2 signaling, leading to sustained induction of IFN stimulatory genes. Integrative genomic analysis depicted strong enrichment of an antiviral gene‐module in CpG‐activated NCoR1 knockdown DCs upon TLR9 activation. Moreover, we confirmed our findings in primary DCs derived from splenocytes of WT and NCoR1 DC−/− animals, which showed protection from Sendai and Vesicular Stomatitis viruses upon CpG activation. Ultimately, we identified that NCoR1–HDAC3 complex is involved in repressing the type‐I IFN response in cDC1 DCs. [ABSTRACT FROM AUTHOR]

Highlights: [•] The Trypanosoma brucei telomerase RNA is a C/D snoRNA that is localized near the nucleolus. [•] TER silencing causes shortening of the chromosomes but no growth arrest. [•] pre-TER is trans-spliced linking trans-splicing to the processing of non-coding RNAs. [Copyright &y& Elsevier]