Assembly of a spatial circuit of T-bet-expressing lymphocytes is required for antiviral humoral immunity
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ABSTRACT:
PROVIDER: PRJNA726250 | ENA |
REPOSITORIES: ENA
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Project description:Effective antiviral immunity requires generation of T and B lymphocytes expressing transcription factor T-bet, a regulator of type 1 inflammatory responses. Using T-bet expression as an endogenous marker for cells participating in a type 1 response, we report coordinated interactions of T-bet-expressing T and B lymphocytes based on their dynamic co-localization at T cell zone and B follicle boundary (T-B boundary) and germinal centers (GC) within the draining lymph node during lung influenza infection. We demonstrate that the assembly of this circuit takes place in distinct anatomical niches, guided by CXCR3, which enables positioning of TH1 cells at the T-B boundary. The encounter of B and TH1 cells at T-B boundary enables IFN produced by the latter to induce IgG2c class switching. Within GCs, T-bet+ TFH cells represent a specialized stable sub-lineage required for GC growth, but dispensable for IgG2c class switching. Our studies show that during respiratory viral infection, T-bet-expressing T and B lymphocytes form a circuit assembled in a spatio-temporally controlled manner that acts as a functional unit enabling a robust and coherent humoral response tailored for optimal antiviral immunity.
2021-04-30 | GSE173605 | GEO
Project description:Effective antiviral immunity requires generation of T and B lymphocytes expressing the transcription factor T-bet, a regulator of type 1 inflammatory responses. Using T-bet expression as an endogenous marker for cells participating in a type 1 response, we report coordinated interactions of T-bet-expressing T and B lymphocytes on the basis of their dynamic colocalization at the T cell zone and B follicle boundary (T-B boundary) and germinal centers (GCs) during lung influenza infection. We demonstrate that the assembly of this circuit takes place in distinct anatomical niches within the draining lymph node, guided by CXCR3 that enables positioning of TH1 cells at the T-B boundary. The encounter of B and TH1 cells at the T-B boundary enables IFN-γ produced by the latter to induce IgG2c class switching. Within GCs, T-bet+ TFH cells represent a specialized stable sublineage required for GC growth but dispensable for IgG2c class switching. Our studies show that during respiratory viral infection, T-bet-expressing T and B lymphocytes form a circuit assembled in a spatiotemporally controlled manner that acts as a functional unit enabling a robust and coherent humoral response tailored for optimal antiviral immunity.
| S-EPMC8418793 | biostudies-literature
Project description:This SuperSeries is composed of the following subset Series: GSE36241: Identification of a FOXO3/IRF7 circuit that limits inflammatory sequelae of antiviral responses (ChIP-Seq) GSE37051: Identification of a FOXO3/IRF7 circuit that limits inflammatory sequelae of antiviral responses (expression) Refer to individual Series
2012-09-19 | E-GEOD-37052 | biostudies-arrayexpress
Project description:We predict that a member of the forkhead family of transcription factors, FOXO3, is a negative regulator of a subset of antiviral genes. This prediction was validated using macrophages isolated from Foxo3-null mice. Genome-wide location analysis combined with gene deletion studies identified the Irf7 gene as a critical target of FOXO3. FOXO3 was identified as a negative regulator of Irf7 transcription. Our data suggest that the FOXO3-IRF7 regulatory circuit represents a novel mechanism for establishing the requisite set points in the interferon pathway. C57BL/6 mice were obtained from Jackson Laboratories. Foxo3-/- mice in the FVB background were obtained from MMRRC and were backcrossed to C57BL/6 mice at least 5 times to generate congenic mice. C57BL/6 Foxo3+/- heterozygotes were intercrossed to generate Foxo3-/- mice. Mice were maintained at the animal facility of the Institute for Systems Biology and used at 8–12 weeks of age. All animals were housed and handled according to the approved protocols of University of Washington and Institute for Systems Biology's Institutional Animal Care and Use Committees.
2012-09-19 | E-GEOD-36241 | biostudies-arrayexpress
Project description:We predict that a member of the forkhead family of transcription factors, FOXO3, is a negative regulator of a subset of antiviral genes. This prediction was validated using macrophages isolated from Foxo3-null mice. Genome-wide location analysis combined with gene deletion studies identified the Irf7 gene as a critical target of FOXO3. FOXO3 was identified as a negative regulator of Irf7 transcription. Our data suggest that the FOXO3-IRF7 regulatory circuit represents a novel mechanism for establishing the requisite set points in the interferon pathway.
2012-09-19 | GSE36241 | GEO
Project description:This study used RNAseq to study the mechanism of cellular and humoral rejection by comparing clinical samples of cellular, humoral, mixed, and normal.
2018-10-16 | GSE74261 | GEO
Project description:Bromodomain and extra-terminal domain (BET) proteins are therapeutic targets in several cancers including the most common malignant adult brain tumor glioblastoma (GBM). Multiple small molecule inhibitors of BET proteins have been utilized in preclinical and clinical studies. Unfortunately, BET inhibitors have not shown efficacy in clinical trials enrolling GBM patients. One possible reason for this may stem from resistance mechanisms that arise after prolonged treatment within a clinical setting. However, the mechanisms and timeframe of resistance to BET inhibitors in GBM is not known. To identify the temporal order of resistance mechanisms in GBM we performed quantitative proteomics using multiplex-inhibitor bead mass spectrometry and demonstrated that resistance to BET inhibitors in GBM treatment occurs rapidly within hours and involves the fibroblast growth factor receptor 1 (FGFR1) protein. Small molecule inhibition of BET proteins and FGFR1 simultaneously induces synergy in reducing GBM tumor growth in vitro and in vivo. Further, FGFR1 knockdown synergizes with BET inhibitor mediated reduction of GBM cell proliferation. Collectively, our studies suggest that co-targeting BET and FGFR1 may dampen resistance mechanisms to yield a clinical response in GBM.
2024-06-16 | PXD043214 | Pride
Project description:Lytic infection by the Epstein-Barr virus (EBV) poses numerous health risks, such as infectious mononucleosis and lymphoproliferative disorder. We demonstrate that JQ1 and other BET inhibitors block two different steps in the sequential cascade of the EBV life cycle: expression of the immediate-early gene BZLF1 and lytic genome replication. This represents a novel mode of action for antiviral drugs that may increase efficacy and decrease emergence of resistance. The sequenced total DNA data below show that JQ1 and I-BET cause a decrease in EBV genome replication after induction.
2017-06-30 | GSE84212 | GEO
Project description:Endothelial function and integrity are compromised after allogeneic bone marrow transplantation (BMT) but how this affects immune responses broadly remains unknown. Using a preclinical model of cytomegalovirus (CMV) reactivation after BMT, we found compromised antiviral humoral responses induced by IL-6 signaling. IL-6 signaling in T cells maintained Th1 cells resulting in sustained IFN secretion which promoted endothelial cell (EC) injury, loss of the neonatal Fc receptor (FcRn) responsible for immunoglobulin G (IgG) recycling, and rapid IgG loss. In contrast, recipient IgG producing cells are rapidly eliminated after BMT. T cell-specific deletion of IL-6R led to persistence of recipient-derived CMV-specific IgG and inhibited CMV reactivation. Deletion of IFN in donor T cells also eliminated EC injury and FcRn loss. In a phase III clinical trial, blockade of IL-6R with tocilizumab promoted CMV-specific IgG persistence and significantly attenuated early HCMV reactivation. In sum, IL-6 invokes IFN-dependent EC injury and consequent IgG loss leading to CMV reactivation. Hence, cytokine inhibition represents a logical strategy to prevent endothelial injury thereby preserving humoral immunity after immunotherapy.
2024-04-01 | GSE252180 | GEO
Project description:Lytic infection by the Epstein-Barr virus (EBV) poses numerous health risks, such as infectious mononucleosis and lymphoproliferative disorder. We demonstrate that JQ1 and other BET inhibitors block two different steps in the sequential cascade of the EBV life cycle: expression of the immediate-early gene BZLF1 and lytic genome replication. This represents a novel mode of action for antiviral drugs that may increase efficacy and decrease emergence of resistance. The ChIP-seq data below show that the BET proteins bind to both EBV lytic origins of replication.
2017-06-30 | GSE84213 | GEO