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Project description:CD8+ T cells are critical mediators of pathogen clearance and anti-tumor immunity. Although signaling pathways leading to the activation of NF-B transcription factors have crucial functions in the regulation of immune responses, the CD8+ T cell-autonomous roles of the different NF-B subunits, are still unresolved. Here, we investigated the function of the ubiquitously expressed transcription factor RelA in CD8+ T-cell biology using a novel mouse model and gene-edited human cells. We found that CD8+ T cell-specific ablation of RelA markedly altered the transcriptome of ex vivo stimulated cells, but maintained the proliferative capacity of both mouse and human cells. In contrast, in vivo experiments showed that RelA deficiency did not affect the CD8+ T-cell response to acute viral infection or transplanted tumors. Our data suggest that in CD8+ T cells, RelA is dispensable for their protective activity in pathological contexts.
2024-02-27 | GSE254684 | GEO
Project description:CD8+ T cells are critical mediators of pathogen clearance and anti-tumor immunity. Although signaling pathways leading to the activation of NF-B transcription factors have crucial functions in the regulation of immune responses, the CD8+ T cell-autonomous roles of the different NF-B subunits, are still unresolved. Here, we investigated the function of the ubiquitously expressed transcription factor RelA in CD8+ T-cell biology using a novel mouse model and gene-edited human cells. We found that CD8+ T cell-specific ablation of RelA markedly altered the transcriptome of ex vivo stimulated cells, but maintained the proliferative capacity of both mouse and human cells. In contrast, in vivo experiments showed that RelA deficiency did not affect the CD8+ T-cell response to acute viral infection or transplanted tumors. Our data suggest that in CD8+ T cells, RelA is dispensable for their protective activity in pathological contexts.
2024-02-27 | GSE254683 | GEO
Project description:CD8+ T cells are critical mediators of pathogen clearance and anti-tumor immunity. Although signaling pathways leading to the activation of NF-κB transcription factors have crucial functions in the regulation of immune responses, the CD8+ T cell-autonomous roles of the different NF-κB subunits, are still unresolved. Here, we investigated the function of the ubiquitously expressed transcription factor RelA in CD8+ T-cell biology using a novel mouse model and gene-edited human cells. We found that CD8+ T cell-specific ablation of RelA markedly altered the transcriptome of ex vivo stimulated cells, but maintained the proliferative capacity of both mouse and human cells. In contrast, in vivo experiments showed that RelA deficiency did not affect the CD8+ T-cell response to acute viral infection or transplanted tumors. Our data suggest that in CD8+ T cells, RelA is dispensable for their protective activity in pathological contexts.
| S-EPMC10948531 | biostudies-literature
Project description:The NF-κB RelA transcription factor is dispensable for CD8+ T-cell function in acute viral infection and cancer
| PRJNA1071515 | ENA
Project description:The NF-κB RelA transcription factor is dispensable for CD8+ T-cell function in acute viral infection and cancer [human]
| PRJNA1071526 | ENA
Project description:The NF-κB RelA transcription factor is dispensable for CD8+ T-cell function in acute viral infection and cancer [mouse]
| PRJNA1071527 | ENA
Project description:Modulators (Ms) are proteins that modify the activity of transcription factors (TFs) and influence expression of their target genes (TGs). To discover modulators of NF-κB/RelA, we first identified 365 NF-κB/RelA-binding proteins using liquid chromatography-tandem mass spectrometry (LC-MS/MS). We used a probabilistic model to infer 8349 (M, NF-κB/RelA, TG) triplets and their modes of modulatory action from our combined LC-MS/MS and ChIP-Seq (ChIP followed by next generation sequencing) data, published RelA modulators and TGs, and a compendium of gene expression profiles. Hierarchical clustering of the derived modulatory network revealed functional subnetworks and suggested new pathways modulating RelA transcriptional activity. The modulators with the highest number of TGs and most non-random distribution of action modes (measured by Shannon entropy) are consistent with published reports. Our results provide a repertoire of testable hypotheses for experimental validation. One of the NF-κB/RelA modulators we identified is STAT1. The inferred (STAT1, NF-κB/RelA, TG) triplets were validated by LC-selected reaction monitoring-MS and the results of STAT1 deletion in human fibrosarcoma cells. Overall, we have identified 562 NF-κB/RelA modulators, which are potential drug targets, and clarified mechanisms of achieving NF-κB/RelA multiple functions through modulators. Our approach can be readily applied to other TFs.
| S-EPMC4002100 | biostudies-literature
Project description:BackgroundThe transcription factor NF-κB consisting of the subunits RelA/p65 and p50 is known to be quickly activated after partial hepatectomy (PH), the functional relevance of which is still a matter of debate. Current concepts suggest that activation of NF-κB is especially critical in non-parenchymal cells to produce cytokines (TNF, IL-6) to adequately prime hepatocytes to proliferate after PH, while NF-κB within hepatocytes mainly bears cytoprotective functions.MethodsTo study the role of the NF-κB pathway in different liver cell compartments, we generated conditional knockout mice in which the transactivating NF-κB subunit RelA/p65 can be inactivated specifically in hepatocytes (Rela(F/F)AlbCre) or both in hepatocytes plus non-parenchymal cells including Kupffer cells (Rela(F/F)MxCre). 2/3 and 80% PH were performed in controls (Rela(F/F)) and conditional knockout mice (Rela(F/F)AlbCre and Rela(F/F)MxCre) and analyzed for regeneration.ResultsHepatocyte-specific deletion of RelA/p65 in Rela(F/F)AlbCre mice resulted in an accelerated cell cycle progression without altering liver mass regeneration after 2/3 PH. Surprisingly, hepatocyte apoptosis or liver damage were not enhanced in Rela(F/F)AlbCre mice, even when performing 80% PH. The additional inactivation of RelA/p65 in non-parenchymal cells in Rela(F/F)MxCre mice reversed the small proliferative advantage observed after hepatocyte-specific deletion of RelA/p65 so that Rela(F/F)MxCre mice displayed normal cell cycle progression, DNA-synthesis and liver mass regeneration.ConclusionThe NF-κB subunit RelA/p65 fulfills opposite functions in different liver cell compartments in liver regeneration after PH. However, the effects observed after conditional deletion of RelA/p65 are small and do not alter liver mass regeneration after PH. We therefore do not consider RelA/p65-containing canonical NF-κB signalling to be essential for successful liver regeneration after PH.
| S-EPMC3462179 | biostudies-literature
Project description:Tumor-associated myeloid cells, including dendritic cells (DCs) and macrophages, are immune suppressive. This study demonstrates a novel mechanism involving FOXO3 and NF-κB RelA that controls myeloid cell signaling and impacts their immune-suppressive nature. We find that FOXO3 binds NF-κB RelA in the cytosol, impacting both proteins by preventing FOXO3 degradation and preventing NF-κB RelA nuclear translocation. The location of protein-protein interaction was determined to be near the FOXO3 transactivation domain. In turn, NF-κB RelA activation was restored upon deletion of the same sequence in FOXO3 containing the DNA binding domain. We have identified for the first time, to our knowledge, a direct protein-protein interaction between FOXO3 and NF-κB RelA in tumor-associated DCs. These detailed biochemical interactions provide the foundation for future studies to use the FOXO3-NF-κB RelA interaction as a target to enhance tumor-associated DC function to support or enhance antitumor immunity.
| S-EPMC4670825 | biostudies-literature
Project description:Considerable evidence supports the prediction that CD25 is directly regulated by the forkhead transcription factor FOXP3. However, given that CD25 is normally upregulated in activated T cells, regardless of whether they express FOXP3, this issue has still to be definitively demonstrated. Here we describe that FOXP3, induced by CD28 signals in human CD4(+)CD25(-) T lymphocytes, synergizes with RelA on a regulatory region of Cd25 promoter to mediate the transcriptional activation of Cd25 gene. We found that a striking feature of this regulatory region is the presence of a κB site and of two tandem copies of a non-consensus FOXP3 binding site separated at 5' ends by 19 nucleotides that allow FOXP3 and RelA binding to DNA and their physical interaction. The occupancy of the two FOXP3 binding sites in conjunction with RelA binding site occupancy allows FOXP3 to function as a positive activator of Cd25 gene. Indeed mutations of both FOXP3 binding sites such as mutation of κB site on Cd25 promoter abolished FOXP3 activatory functions. Moreover, FOXP3 mutation ΔE251, that compromises FOXP3 homotypic interactions, failed to trans activate Cd25 promoter, suggesting that both FOXP3 DNA binding and dimerization are required to trans activate Cd25 promoter. These findings identify a novel mechanism by which RelA and FOXP3 cooperate to mediate transcriptional regulation of target genes and characterize a region on Cd25 promoter where FOXP3 dimer could bridge intramolecularly two DNA sites and trans activate Cd25 gene.
| S-EPMC3483148 | biostudies-literature