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Host resistance against intracellular pathogens requires a rapid IFN-γ mediated immune response. We reveal that T-bet-dependent production of IFN-γ is essential for the maintenance of inflammatory DCs at the site of infection with a common protozoan parasite, Toxoplasma gondii . A detailed analysis of the cellular sources for T-bet-dependent IFN-γ identified that ILC1s and to a lesser degree NK, but not T H 1 cells, were involved in the regulation of inflammatory DCs via IFN-γ. Mechanistically, we established that T-bet dependent innate IFN-γ is critical for the induction of IRF8, an essential transcription factor for cDC1s. Failure to upregulate IRF8 in DCs resulted in acute susceptibility to T . gondii infection. Our data identifies that T-bet dependent production of IFN-γ by ILC1 and NK cells is indispensable for host resistance against intracellular infection via maintaining IRF8+ inflammatory DCs at the site of infection.

Interferon regulatory factor 8 (IRF8), also known as interferon consensus sequence-binding protein (ICSBP), is a transcription factor of the IRF family. IRF8 plays a key role in normal B cell differentiation, a cellular process that is intrinsically associated with Epstein-Barr virus (EBV) reactivation. However, whether IRF8 regulates EBV lytic replication remains unknown. In this study, we utilized a CRISPR/Cas9 genomic editing approach to deplete IRF8 and found that IRF8 depletion dramatically inhibits the reactivation of EBV upon lytic induction. We demonstrated that IRF8 depletion suppresses the expression of a group of genes involved in apoptosis and thus inhibits apoptosis induction upon lytic induction by B cell receptor (BCR) stimulation or chemical induction. The protein levels of caspase-1, caspase-3 and caspase-8 all dramatically decreased in IRF8-depleted cells, which led to reduced caspase activation and the stabilization of KAP1, PAX5 and DNMT3A upon BCR stimulation. Interestingly, caspase inhibition blocked the degradation of KAP1, PAX5 and DNMT3A, suppressed EBV lytic gene expression and viral DNA replication upon lytic induction, suggesting that the reduced caspase expression in IRF8-depleted cells contributes to the suppression of EBV lytic replication. We further demonstrated that IRF8 directly regulates CASP1 (caspase-1) gene expression through targeting its gene promoter and knockdown of caspase-1 abrogates EBV reactivation upon lytic induction, partially through the stabilization of KAP1. Together our study suggested that, by modulating the activation of caspases and the subsequent cleavage of KAP1 upon lytic induction, IRF8 plays a critical role in EBV lytic reactivation.

Several modulatory factors in the TLR signaling pathway including IRF3, IRF7, IRF8, TRIM20, MYD88 and NF-κB1 have been associated with autoimmune disease. In this study, we investigated the association of 13 SNPs for these genes with Behçet’s disease (BD) and Vogt-Koyanagi-Harada (VKH) syndrome using a polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) assay. Haplotype and linkage disequilibrium (LD) analysis were performed by Haploview4.2. IRF8 mRNA expression and cytokine production was tested by real-time PCR and ELISA. Two SNPs near IRF8 were associated with BD (for rs17445836 GG genotype, Pc = 9.56 × 10 −8 , OR = 2.044; for rs11642873 AA genotype, Pc = 9.24 × 10 −7 , OR = 1.776). No significant association was found for the 13 SNPs tested with VKH syndrome. Haplotype analysis of the two positive SNPs revealed that the AG haplotype was significantly increased in BD patients (Pc = 2.60 × 10 −8 , OR = 1.646). Functional studies revealed an increased mRNA expression of IRF8 and IFN-γ production and a decreased production of IL-10 in rs17445836 carriers with the GG genotype. Increased expression of IRF8 as well as IFN-γ production and a decreased production of IL-10 were found in individuals carrying the rs11642873/AA genotype. In conclusion, this study indicates that IRF8 may contribute to the genetic susceptibility of BD by regulating IRF8 expression and cytokine production.

The present study aimed to investigate gene expression profile alterations associated with cysteine‑rich 61 (CYR61) expression in human glioma cells. The GSE29384 dataset, downloaded from the Gene Expression Omnibus, includes three LN229 human glioma cell samples expressing CYR61 induced by doxycycline (Dox group), and three control samples not exposed to doxycycline (Nodox group). Differentially expressed genes (DEGs) between the Dox and Nodox groups were identified with cutoffs of |log2 fold change (FC)|>0.5 and P<0.05. Gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses for DEGs were performed. Protein‑protein interaction (PPI) network and module analyses were performed to identify the most important genes. Transcription factors (TFs) were obtained by detecting the TF binding sites of DEGs using a Whole Genome rVISTA online tool. A total of 258 DEGs, including 230 (89%) upregulated and 28 (11%) downregulated DEGs were identified in glioma cells expressing CYR61 compared to cells without CYR61 expression. The majority of upregulated DEGs, including interferon (IFN)B1, interferon‑induced (IFI)44 and interferon regulatory factor (IRF)7, were associated with immune, defense and virus responses, and cytokine‑cytokine receptor interaction signaling pathways. Signal transducer and activator of transcription 1 (STAT1) and DEAD‑box helicase 58 (DDX58) were observed to have high connection degrees in the PPI network. A total of seven TFs of the DEGs, including interferon consensus sequence‑binding protein and IFN‑stimulated gene factor‑3 were additionally detected. In conclusion, IFNB1, genes encoding IFN‑induced proteins (IFI16, IFI27, IFI44 and IFITM1), IRFs (IRF1, IRF7 and IRF9), STAT1 and DDX58 were demonstrated to be associated with CYR61 expression in glioma cells; thus, they may be critical for maintaining the role of CYR61 during cancer progression.

Mice lacking transcription factor i nterferon c onsensus s equence b inding p rotein (ICSBP) develop a syndrome similar to human chronic myeloid leukemia and are immunodeficient. In order to define the molecular mechanisms responsible for the cellular defects of ICSBP −/− mice, we used bone marrow‐derived macrophages (BMM) to identify genes deregulated in the absence of ICSBP. Here, we report that disabled‐2 (Dab2), a signal phosphoprotein, is transcriptionally up‐regulated and accumulates in the cytoskeleton/membrane fraction of ICSBP −/− BMM. Moreover, our results revealed Dab2 as a novel IFN‐γ‐response gene. Both ICSBP and the Ets‐transcription factor PU.1 bind to the Dab2 promoter, whereby ICSBP represses PU.1‐induced Dab2 promoter transactivation in vitro . Notably, repression of Dab2 expression by ICSBP is also found in myeloid progenitors. Overexpression of Dab2 leads to accelerated cell adhesion and spreading, accompanied by enhanced actin fiber formation. Furthermore, cell adhesion induces transient Dab2 phosphorylation and its translocation to the cytoskeletal/membrane fraction. Our results identify a novel role of Dab2 as an inducer of cell adhesion and spreading, and strongly suggest that the up‐regulation of Dab2 contributes to the hematopoietic defect seen in ICSBP −/− mice.

Identifying genetic pathways that cooperate in leukemogenesis facilitates our understanding of the molecular mechanisms at play. Interferon consensus sequence-binding protein (ICSBP) is a tumor suppressor, whose downregulation cooperates with BCR-ABL and NUP98-TOP1 gene products to accelerate leukemia induction in mouse models. Similarly, Meis1 synergizes with HoxA9 or NUP98-HOX (but not NUP98-TOP1 ) fusion genes to promote the early onset of leukemia. To investigate whether Icsbp deficiency interacts with Meis1 or its family member Meis3 , we transplanted Icsbp −/− bone marrow (BM) cells after transduction with Meis1 or Meis3 retroviral vectors. Here, we show that enforced expression of Meis1 or Meis3 in Icsbp −/− BM cells induces a fatal, invasive myeloproliferative disease. Secondary mutations, such as activation of Mn1 , led to the progression to acute myeloid leukemia in a few mice. Interestingly, expression of endogenous Meis1 and Meis3 mRNAs was repressed in the granulocytic progenitor population of Icsbp −/− mice. These results reveal a novel collaboration between Icsbp deficiency and Meis1 / Meis3 in the acceleration of chronic myeloid leukemia-like disease.