Retinoic acid receptor-related orphan receptor α regulates bystander activation of memory CD8+ T cells
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PROVIDER: PRJNA1300295 | ENA |
REPOSITORIES: ENA
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Project description:Background: Memory CD8+ T cells sense inflammation and rapidly produce interferon-γ (IFN-γ) independent of cognate antigens. This innate-like property, called bystander activation, is involved in early host defense before the antigen-specific memory response. However, the molecular mechanisms underlying this activation remain unknown. Retinoic acid receptor-related orphan receptor α (RORα) belongs to the nuclear receptor family and regulates gene transcription in ligand-dependent manner. Although RORα is highly expressed in memory CD8+ T cells, its functional relevance has not been investigated. Methods: Primary and secondary memory T cells that are sufficient or deficient of RORα were induced by adoptive transfer of naïve OT-I T cells to recipient mice and subsequent infection with Listeria monocytogenes expressing ovalbumin (LM-OVA). RORα expression in memory T cells were examined by quantitative PCR. The target genes of RORα in memory T cells were explored by RNA-sequencing and verified by RORα overexpression in postactivated T cells. The impact of RORα-deficiency on bystander activation was assessed by stimulating memory T cells with inflammatory cytokines in vitro or injecting lipopolysaccharide (LPS) into mice bearing memory T cells. Results: RORα expression was remarkably elevated in secondary memory CD8+ T cells along with the enrichment of effector-like memory T cells. RORα primarily acted as a transcription factor in regulating the gene expression of the TL1A receptor. RORα deficiency abrogated the IFN-γ production by memory CD8+ T cells in response to IL-12 + TL1A in vitro and diminished the bystander response to LPS-induced inflammation in vivo. Conclusion: This study revealed a regulatory mechanism of bystander activation. The findings also improve our understanding of how memory T cells increase their immediate protective capacity through repeated infections and vaccinations.
2025-08-03 | GSE304290 | GEO
Project description:Retinoic acid receptor-related orphan receptor α regulates bystander activation of memory CD8+ T cells [RNA-Seq]
| PRJNA1299279 | ENA
Project description:Background: Memory CD8+ T cells sense inflammation and rapidly produce interferon-γ (IFN-γ) independent of cognate antigens. This innate-like property, called bystander activation, is involved in early host defense before the antigen-specific memory response. However, the molecular mechanisms underlying this activation remain unknown. Retinoic acid receptor-related orphan receptor α (RORα) belongs to the nuclear receptor family and regulates gene transcription in ligand-dependent manner. Although RORα is highly expressed in memory CD8+ T cells, its functional relevance has not been investigated. Methods: Primary and secondary memory T cells that are sufficient or deficient of RORα were induced by adoptive transfer of naïve OT-I T cells to recipient mice and subsequent infection with Listeria monocytogenes expressing ovalbumin (LM-OVA). RORα expression in memory T cells were examined by quantitative PCR. The target genes of RORα in memory T cells were explored by RNA-sequencing and verified by RORα overexpression in postactivated T cells. The impact of RORα-deficiency on bystander activation was assessed by stimulating memory T cells with inflammatory cytokines in vitro or injecting lipopolysaccharide (LPS) into mice bearing memory T cells. Results: RORα expression was remarkably elevated in secondary memory CD8+ T cells along with the enrichment of effector-like memory T cells. RORα primarily acted as a transcription factor in regulating the gene expression of the TL1A receptor. RORα deficiency abrogated the IFN-γ production by memory CD8+ T cells in response to IL-12 + TL1A in vitro and diminished the bystander response to LPS-induced inflammation in vivo. Conclusion: This study revealed a regulatory mechanism of bystander activation. The findings also improve our understanding of how memory T cells increase their immediate protective capacity through repeated infections and vaccinations.
2025-08-07 | GSE304146 | GEO
Project description:About one-third of oestrogen receptor alpha- positive breast cancer patients treated with tamoxifen relapse. Here we identify the nuclear receptor retinoic acid receptor alpha as a marker of tamoxifen resistance. Using quantitative mass spectrometry-based proteomics, we show that retinoic acid receptor alpha protein networks and levels differ in a tamoxifen-sensitive (MCF7) and a tamoxifen-resistant (LCC2) cell line. High intratumoural retinoic acid receptor alpha protein levels also correlate with reduced relapse-free survival in oestrogen receptor alpha-positive breast cancer patients treated with adjuvant tamoxifen solely. A similar retinoic acid receptor alpha expression pattern is seen in a comparable independent patient cohort. An oestrogen receptor alpha and retinoic acid receptor alpha ligand screening reveals that tamoxifen-resistant LCC2 cells have increased sensitivity to retinoic acid receptor alpha ligands and are less sensitive to oestrogen receptor alpha ligands compared with MCF7 cells. Our data indicate that retinoic acid receptor alpha may be a novel therapeutic target and a predictive factor for oestrogen receptor alpha-positive breast cancer patients treated with adjuvant tamoxifen. Peptide and protein identification data set 1: Peptide identification from the MALDI-TOF/TOF data was carried out using the Paragon algorithm in the ProteinPilot 2.0 software package (Applied Biosystems) 46. Default settings for a 4800 instrument were used (i.e., no manual settings for mass tolerance was given). The following parameters were selected in the analysis method: iTRAQ 4plex peptide labelled as sample type, MMTS as alkylating agent of cysteine, trypsin as digesting enzyme, 4800 as instrument, gel based ID and Urea denaturation as special factors, biological modifications as ID focus, and thorough ID as search effort. Peptide identification from the Q-TOF data was carried out using the Spectrum Mill Protein Identification software (Agilent). Data was extracted between MH+ 600 and 4000 Da (Agilent's definition). Scans with the same precursor m/z 90 sec, 0.05 m/z matching with a minimum of 20 peaks in MS2 were merged. Peptide and protein identification data set 2: Proteome discoverer 1.3 with sequest-percolator was used for protein identification. Precursor mass tolerance was set to 10 ppm and for fragments 0.8 Da and 0.02 Da were used for detection in the linear iontrap and the orbitrap, respectively. Oxidized methionine and phosphorylation on S,T and Y was set as dynamic modifications, and carbamidomethylation, N-terminal 8plex iTRAQ, and lysyl 8plex iTRAQ as fixed modifications. Spectra were matched to ensembl 68 limited to human protein sequences, and results were filtered to 1% FDR.
2013-07-24 | PXD000281 | Pride
Project description:Retinoic acid-related Orphan Receptor alpha (RORalpha; NR1F1) is a nuclear receptor involved in several physiological and patho-physiological functions including lipid metabolism, inflammation, angiogenesis, and circadian rythm. It is widely distributed. In order to better understand the role of this nuclear receptor in liver, we aimed at displaying genes controlled by RORalpha in liver cells. HepG2 human hepatoma cells stably over-expressing RORalpha were designed. Genes whose expression was altered in these cells versus control cells were displayed using micro-arrays and qRT-PCR. Expression of these genes was also altered in cells in which RORalpha was transiently over-expressed after adenoviral infection. Some genes are involved in functions controlled by RORalpha. This is the case for LPA, NR1D2 and ADIPOQ in lipid metabolism, ADIPOQ and PLG in inflammation, PLG in fibrinolysis and NR1D2 and NR1D1 in circadian rhythm. This study also revealed that genes such as G6PC, involved in glucose homeostasis, and AGRP, involved in the control of body weight, are also controlled by RORalpha. Lastly, SPARC, involved in cell growth and adhesion and associated with liver carcinogenesis, was up-regulated by RORalpha. It is a new direct RORalpha target gene since it possesses, in its promoter, a functional RORE as evidenced by EMSAs and transfection experiments. It is likely the case for most of the other genes we found regulated by RORalpha contain putative ROREs in their regulatory regions. These results open new routes to think about the role of RORalpha in glucose metabolism and carcinogenesis within cells of hepatic origin. Keywords: Comparison of HepG2 cells expressing RORalpha or control HepG2 cells cultured in 20% oxygen or 2% oxygen during 24h.
2009-11-04 | GSE18875 | GEO
Project description:Highly pathogenic influenza virus inhibit Inflammatory Responses in Monocytes via Activation of the Rar-Related Orphan Receptor Alpha (RORalpha). Low (PR8) and high pathogenic influenza viruses (FPV and H5N1) were used. Monocytes were infected with low (PR8) and high pathogenic influenza viruses (FPV and H5N1)
2013-07-01 | E-GEOD-35283 | biostudies-arrayexpress
Project description:Retinoic acid receptor-alpha (RAR alpha) is a known estrogen target gene in breast cancer cells. The consequence of RAR alpha induction by estrogen was previously unknown. We now show that RAR alpha is required for efficient estrogen receptor-alpha (ER)-mediated transcription and cell proliferation. RAR alpha can interact with ER-binding sites, but this occurs in an ER-dependent manner, providing a novel role for RAR alpha that is independent of its classic role. We show, on a genome-wide scale, that RAR alpha and ER can co-occupy regulatory regions together within the chromatin. This transcriptionally active co-occupancy and dependency occurs when exposed to the predominant breast cancer hormone, estrogen--an interaction that is promoted by the estrogen-ER induction of RAR alpha. These findings implicate RAR alpha as an essential component of the ER complex, potentially by maintaining ER-cofactor interactions, and suggest that different nuclear receptors can cooperate for effective transcriptional activity in breast cancer cells. RAR alpha silenced breast cancer MCF-7 cell lines or control siRNA in the presence of estrogen or a vehicle. MCF-7 cells were hormone-depleted for 3 d and treated with 100 nM estrogen for 12 h. There were three biological replicates for each of the four different groups.
2010-06-16 | E-GEOD-22213 | biostudies-arrayexpress
Project description:Highly pathogenic influenza virus inhibit Inflammatory Responses in Monocytes via Activation of the Rar-Related Orphan Receptor Alpha (RORalpha). Low (PR8) and high pathogenic influenza viruses (FPV and H5N1) were used.
2013-07-01 | GSE35283 | GEO
Project description:Retinoic acid receptor-alpha (RAR alpha) is a known estrogen target gene in breast cancer cells. The consequence of RAR alpha induction by estrogen was previously unknown. We now show that RAR alpha is required for efficient estrogen receptor-alpha (ER)-mediated transcription and cell proliferation. RAR alpha can interact with ER-binding sites, but this occurs in an ER-dependent manner, providing a novel role for RAR alpha that is independent of its classic role. We show, on a genome-wide scale, that RAR alpha and ER can co-occupy regulatory regions together within the chromatin. This transcriptionally active co-occupancy and dependency occurs when exposed to the predominant breast cancer hormone, estrogen--an interaction that is promoted by the estrogen-ER induction of RAR alpha. These findings implicate RAR alpha as an essential component of the ER complex, potentially by maintaining ER-cofactor interactions, and suggest that different nuclear receptors can cooperate for effective transcriptional activity in breast cancer cells.
2010-06-09 | GSE22213 | GEO
Project description:The existence of a radiation bystander effect, in which non-irradiated cells respond to signals from irradiated cells, is well established. It raises concerns for the interpretation of risks from exposure to low doses of ionizing radiation. Sparse data exists about the bystander signaling mechanisms and the ability to transmit damaging effects both spatially and temporally. To understand early signaling and cellular changes in bystanders, we have measured global gene expression 30 minutes after direct and bystander exposure to alpha particle in primary human lung fibroblasts. Gene ontology and pathway analyses suggested that the earliest measured changes at 30 minutes after treatment are in cell structure, motility and adhesion categories and a significant number of genes belong to the category of inflammation and cell-to-cell communication. We investigated time course gene expression profiles of matrix metalloproteinases 1 and 3 (MMP1 and MMP3), chemokine ligands 2, 3 and 5 (CXCL2, CXCL3 and CXCL5), interleukins 1a, 1b, 6 and 33 (IL1A, IL1B, IL6 and IL33) growth differentiation factor 15 (GDF15) and superoxide dismutase2 (SOD2) by real time quantitative PCR. These encode proteins involved in cellular signaling via the NFkappaB pathway and time course of mRNA levels revealed an increased response at 30 minutes after irradiation followed by another wave at 4 to 6 hours. We also investigated protein modifications in the AKT-GSK-3 signaling pathway and found that in irradiated cells AKT and GSK3beta are hyper-phosphorylated at 30 minutes and this effect is maintained until 4 hours after exposure. In bystanders there is a similar response with a delay of 30 minutes. In irradiated cells, inactivated GSK3beta led to decreased phosphorylation of beta-catenin. Our results are the first to show that the radiation induced bystander signal can induce a widespread gene expression response as early as 30 minutes after exposure and that these changes are accompanied by protein modification of signaling modules such as AKT and GSK3beta. There are 12 total samples, 4 corresponding biological replicates of IMR90 cells that were not irradiated (control=C), irradiated (alpha=A) and bystander (B), cells were harvested 0.5 hr after treatment
2010-07-21 | E-GEOD-18760 | biostudies-arrayexpress