IFN-III primes pDCs for TLR7 activation and antagonizes TGF-β mediated-immune suppression in tumors.
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ABSTRACT:
PROVIDER: PRJNA996983 | ENA |
REPOSITORIES: ENA
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Project description:Conventional dendritic cell (cDC1, cDC2) and plasmacytoid dendritic cell (pDCs) subsets have specialized functions that can be modulated by the tumor microenvironment (TME). These cells produce different interferons that are central to antitumor immune responses. While the role of Type I Interferons (IFN-I) in tumor immunity is well characterized, the role of Type III interferons (IFN-III) produced by cDC1 in the TME and associated with good outcome remains completely unknown. Here, we demonstrate that IFN-III orchestrates pDCs survival, activation and TLR7 expression in the blood and in tumors, enhancing their capacity to respond to TLR7-ligand. Importantly, IFN-III prevents the inhibition of pDCs induced by the TME or by TGF-β, a dominant TME inhibitory cue, and restores their production of IFN-⍺. Because of the essential role of TGF-β in immune regulation, this mechanism is expected to impact other pathological situations.
2025-01-08 | GSE237879 | GEO
Project description:Plasmacytoid dendritic cells (pDCs) can be activated by the endosomal TLRs, and contribute to the pathogenesis of systemic lupus erythematosus (SLE) by producing type I IFNs. Thus, blocking TLR-mediated pDC activation may represent a useful approach for the treatment of SLE. In an attempt to identify a therapeutic target for blocking TLR signaling in pDCs, we investigated the contribution of Bruton's tyrosine kinase (Btk) to the activation of pDCs by TLR7 and TLR9 stimulation by using a selective Btk inhibitor RN486. Stimulation of TLR7 and 9 with their respective agonist, namely, gardiquimod and type A CpG ODN2216, resulted in the activation of human pDCs, as demonstrated by the expression of activation markers (CD69, CD40, and CD86), elevated production of IFN-alpha and other inflammatory cytokines, as well as up-regulation of numerous genes including IFN-alpha-inducible genes and activation of interferon regulatory factor 7 (IRF7) and NF-kB. RN486 inhibited all of these events induced by TLR9, but not TLR7 stimulation, with a nanomolar potency for inhibiting type A CpG ODN2216-mediated production of cytokines (e.g., IC50=386 nM for inhibiting IFN-alpha). Our data reveal Btk as an important regulatory enzyme in the TLR9 pathway, and a potential therapeutic target for SLE and other TLR-driven diseases. pDCs from healthy donors (n=4) were treated with gardiquimod (TLR7 agonist) or ODN 2216 (TLR9 agonist) with or without BTK inhibitor for 3 hours.
2015-10-24 | E-GEOD-41825 | biostudies-arrayexpress
Project description:Plasmacytoid dendritic cells (pDCs) can be activated by the endosomal TLRs, and contribute to the pathogenesis of systemic lupus erythematosus (SLE) by producing type I IFNs. Thus, blocking TLR-mediated pDC activation may represent a useful approach for the treatment of SLE. In an attempt to identify a therapeutic target for blocking TLR signaling in pDCs, we investigated the contribution of Bruton's tyrosine kinase (Btk) to the activation of pDCs by TLR7 and TLR9 stimulation by using a selective Btk inhibitor RN486. Stimulation of TLR7 and 9 with their respective agonist, namely, gardiquimod and type A CpG ODN2216, resulted in the activation of human pDCs, as demonstrated by the expression of activation markers (CD69, CD40, and CD86), elevated production of IFN-alpha and other inflammatory cytokines, as well as up-regulation of numerous genes including IFN-alpha-inducible genes and activation of interferon regulatory factor 7 (IRF7) and NF-kB. RN486 inhibited all of these events induced by TLR9, but not TLR7 stimulation, with a nanomolar potency for inhibiting type A CpG ODN2216-mediated production of cytokines (e.g., IC50=386 nM for inhibiting IFN-alpha). Our data reveal Btk as an important regulatory enzyme in the TLR9 pathway, and a potential therapeutic target for SLE and other TLR-driven diseases.
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Project description:The purpose of this experiment was to assess the genes upregulated when pDCs were stimulated with TLR7 agonist imiquimod and TLR9 agonist CpG C. pDCs were isolated from six healthy donors by FACS sorting, and were stimulated with CpG and imiquimod for 18 hours, after which RNA was extracted for next generation sequencing on the Illumina HiSeq platform. Unstimulated samples were included as controls.
2016-03-17 | E-GEOD-79272 | biostudies-arrayexpress
Project description:The purpose of this experiment was to assess the genes upregulated when pDCs were stimulated with TLR7 agonist imiquimod and TLR9 agonist CpG C.
2016-03-17 | GSE79272 | GEO
Project description:Type I interferons (IFN-I) are important mediators of antiviral immunity and autoimmune diseases. Plasmacytoid dendritic cells (pDCs) from females exert an elevated capacity to produce IFN-I in response to activation of toll-like receptor 7 (TLR7) compared to male pDCs, and both hormones and genes encoded by the X chromosome have been implicated in these sex-specific differences. Using longitudinal samples collected from a cohort of trans men receiving testosterone injections as gender-affirming hormone therapy (GAHT), the impact of testosterone on TLR7-mediated IFN-I production by pDCs was assessed. GAHT induced testosterone and estradiol levels within male reference ranges and increased hemoglobin and hematocrit levels, demonstrating biological activity of testosterone. scRNA seq of pDCs showed downregulation of IFN-I-related gene expression signatures, but also revealed inter-donor heterogeneity on the transcriptional level. Longitudinal quantification of IFN-I protein production by pDCs following TLR7-stimulation showed significant and continuous reduction of IFN-I production in trans men, and reduced expression of IFN-I-stimulated genes. These longitudinal studies in trans men demonstrate that testosterone can reduce IFN-I production by pDCs, and provide novel insights into the immune-modulatory role of testosterone in sex differential IFN-I-mediated immune responses.
2023-11-09 | GSE231370 | GEO
Project description:Toll-like receptor 7 (TLR7) plays a key role in the recognition of RNA viruses and the subsequent induction of an innate immune response. TLR7 contains two ligand binding pockets that recognize distinct RNA degradation products: Pocket 1 recognizes guanosine nucleotides and pocket 2 coordinates short, pyrimidine-rich RNA fragments, while the engagement of both pockets is required to activate TLR7. How these ligands are generated within the endolysosomal compartment is currently unknown. Using a pDC cell line, we here show that the endonuclease RNase T2 and the 5' exonucleases PLD3 and PLD4 act in concert to produce these ligands. On the one hand, RNase T2 generates 2',3'-cyclophosphate-guanosine terminated RNA fragments upon which PLD exonuclease activity acts to release the terminal 2',3'-cyclic GMP. This molecule serves as the physiological ligand for the first binding pocket. On the other hand, PLD activity is also required to generate short RNA fragments that occupy the second binding pocket of TLR7. While PLD3 and PLD4 exert comparable catalytic activities, the almost exclusive expression of PLD4 in pDCs suggests that PLD4 is the relevant exonuclease for pDC activation in the human system. Biochemical and structural studies of PLD3 and PLD4 show that these enzymes form homodimers with two ligand binding sites. Dimer formation is critical for catalytic activity, and previously identified disease-associated mutants fail to form stable dimers. In conclusion, our data provide a mechanistic basis for the recognition of RNA fragments by TLR7.
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2024-04-29 | PXD051868 |
Project description:TLR7/9 signals are capable of mounting massive interferon (IFN) response in plasmacytoid dendritic cells (pDCs) immediately after viral infection, yet the involvement of epigenetic regulation in this process has not been documented. Here, we report that zinc finger CXXC family epigenetic regulator CXXC5 is highly expressed in pDCs, where it plays a crucial role in TLR7/9- and virus-induced IFN response. Notably, genetic ablation of CXXC5 resulted in aberrant methylation of the CpG-containing island (CGI) within the Irf7 gene and impaired IRF7 expression in steady-state pDCs. Mechanistically, CXXC5 is responsible for the recruitment of DNA demethylase Tet2 to maintain the hypomethylation of a subset of CGIs, a process coincident with active histone modifications and constitutive transcription of these CGI-containing genes. Consequently, CXXC5-deficient mice had compromised early IFN response and became highly vulnerable to infection by herpes simplex virus and vesicular stomatitis virus. Together, our results identify CXXC5 as a novel epigenetic regulator for pDC-mediated antiviral response.
| S-EPMC5413332 | biostudies-literature