The USP7-STAT3-granzyme-Par-1 axis regulates allergic inflammation by promoting differentiation of IL-5-producing Th2 cells
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PROVIDER: PRJNA956511 | ENA |
REPOSITORIES: ENA
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Project description:Uncontrolled type 2 immunity by type 2 helper T (Th2) cells causes intractable allergic diseases; however, whether the interaction of CD4+ T cells shapes the pathophysiology of allergic diseases remains unclear. We identified a subset of Th2 cells that produced the serine proteases granzyme A and B early in differentiation. Granzymes cleave protease-activated receptor (Par)-1 and induce phosphorylation of p38 mitogen-activated protein kinase (MAPK), resulting in the enhanced production of IL-5 and IL-13 in both mouse and human Th2 cells. Ubiquitin-specific protease 7 (USP7) regulates IL-4-induced phosphorylation of STAT3, resulting in granzyme production during Th2 cell differentiation. Genetic deletion of Usp7 or Gzma and pharmacological blockade of granzyme B ameliorated allergic airway inflammation. Furthermore, PAR-1+ and granzyme+ Th2 cells were colocalized in nasal polyps from patients with eosinophilic chronic rhinosinusitis. Thus, the USP7-STAT3-granzymes-Par-1 pathway is a potential therapeutic target for intractable allergic diseases.
2023-11-13 | GSE229875 | GEO
Project description:Transcriptome analyses of wildtype and Notch-deficient Th2 cells from mouse models of allergic airway inflammation.
2020-06-08 | GSE125358 | GEO
Project description:Polyfunctional Th2 cells play a crucial role in triggering diverse pathogenic responses in allergic diseases by producing multiple cytokines. However, the precise mechanism underlying their polyfunctionality remains elusive. In this study, we elucidate the pivotal role of Nrf2 in polyfunctional Th2 cells during allergic asthma. We found that an increase in reactive oxygen species (ROS) in immune cells infiltrating the lungs is necessary for the development of eosinophilic asthma. Deletion of the ROS sensor Nrf2 specifically in T cells, but not in dendritic cells, significantly abolished eosinophilia and polyfunctional Th2 cells in the airway. Mechanistically, Nrf2 intrinsic to T cells is essential for inducing optimal oxidative phosphorylation and glycolysis capacity, thereby driving Th2 cell polyfunctionality, partially by inducing PPARγ, independently of IL-33. Treatment with an Nrf2 inhibitor leads to a substantial decrease in polyfunctional Th2 cells and subsequent eosinophilia in mice, and a reduction in the production of Th2 cytokines from peripheral blood mononuclear cells (PBMCs) in asthmatic patients. These findings highlight the critical role of Nrf2 as a spatial and temporal metabolic hub that is essential for polyfunctional Th2 cells, suggesting potential therapeutic implications for allergic diseases.
2023-08-25 | GSE241355 | GEO
Project description:Polyfunctional T cell responses are detrimental in immune disorders; however, it is unclear how effector T cell subsets acquire polyfunctionality in tissues. Here, we demonstrate that the activation of Nrf2 is necessary for the differentiation polyfunctional Th2 cells in vivo. Reactive oxygen species (ROS) levels are significantly elevated in lung-infiltrating immune cells during allergic asthma, and inhibiting either ROS or Nrf2 significantly decreases eosinophilia and polyfunctional Th2 cells in the lung. In vivo studies using multiple cell-type specific Nrf2-deficient mice and mixed bone marrow chimeras revealed that cell-intrinsic Nrf2 drives IL-5 and IL-13 expression in Th2 cells independently of IL-33. Mechanistically, Nrf2 promotes optimal OXPHOS and glycolysis capacity by inducing PPARg expression and glucose uptake to drive polyfunctionality of Th2 cells. Blocking Nrf2 reduces IL-5 and IL-13 production from house dust mite allergen-specific Th2 cells obtained from asthma patients. These findings demonstrate that Nrf2 acts as a spatiotemporal metabolic hub driving the differentiation of polyfunctional Th2 cells, which may have therapeutic implications for controlling allergic lung inflammation.
2023-08-24 | GSE241138 | GEO
Project description:Allergic asthma and rhinitis are two common chronic allergic diseases that affect the lungs and nose, respectively. Both diseases share clinical and pathological features characteristic of excessive allergen-induced type 2 inflammation, orchestrated by memory CD4+ T cells that produce type 2 cytokines (TH2 cells). However, a large majority of subjects with allergic rhinitis do not develop asthma, suggesting divergence in disease mechanisms. Since TH2 cells play a pathogenic role in both these diseases and are also present in healthy non-allergic subjects, we performed global transcriptional profiling to determine whether there are qualitative differences in TH2 cells from subjects with allergic asthma, rhinitis and healthy controls. TH2 cells from asthmatic subjects expressed higher levels of several genes that promote their survival as well as alter their metabolic pathways to favor persistence at sites of allergic inflammation. In addition, genes that enhanced TH2 polarization and TH2 cytokine production were also upregulated in asthma. Several genes that oppose T cell activation were downregulated in asthma, suggesting enhanced activation potential of TH2 cells from asthmatic subjects. Many novel genes with poorly defined functions were also differentially expressed in asthma. Thus, our transcriptomic analysis of circulating TH2 cells has identified several molecules that are likely to confer pathogenic features to TH2 cells that are either unique or common to both asthma and rhinitis.
2016-06-01 | GSE75011 | GEO
Project description:Microarry from Treg with conditional knockout of Usp7 RNA from three independent samples from FACS sorted CD4+YFP+ Treg of fl-Usp7/Foxp3cre mice, compared to Foxp3cre control (C57BL/6 background).
2015-09-15 | E-GEOD-72988 | biostudies-arrayexpress
Project description:USP7, a dominant DUB activity in 3T3-L1 adipocytes and in mouse adipose tissue, increases Tip60 protein levels, and deubiquitinates Tip60 both in intact cells and in vitro. Treatment with a pan deubiquitinase (DUB) inhibitor, or knockdown of USP7, decreases adipogenesis. Transcriptome analysis reveals a common set of cell cycle genes to be co-regulated by both Tip60 and USP7. Knock down of either factor results in impaired mitotic clonal expansion, an early step in adipogenesis. These results therefore reveal deubiquitination of a transcriptional coregulator to be a key mechanism in the regulation of early adipogenesis Mature 3T3-L1 adipocytes were subjected to RNAi-mediated knock down with control(C), USP7(U)- or Tip60(T)-specific oligonucleotides. For this, 4 replicates of differentiated 3T3-L1 cells were transfected with Amaxa technology. Two days after transfection cells were washed twice with PBS twice and lysed in 0.5ml Trizol (Invitrogen). mRNA expression of Tip60 and USP7 was assessed by qRT-PCR. Amplified cRNA samples were labeled with either cy3 or cy5 and put on microarray together with and oppositely labeled common reference sample consisting of cRNA derived from undifferentiated 3T3-L1 cells.
2013-08-28 | E-GEOD-28587 | biostudies-arrayexpress
Project description:In this experiment, we sought to identify the distribution of USP7 on chromatin relative to other PRC1 components ChIP-seq for USP7 in 293T-REx cells
2015-06-10 | E-GEOD-61048 | biostudies-arrayexpress
Project description:Androgens Alleviate Allergic Airway Inflammation by Suppressing Cytokine Production of Th2 Cells
| PRJNA826897 | ENA
Project description:Background: Allergic rhinitis is a growing problem worldwide and the only treatment that modifies the cause of the disease is antigen-specific immunotherapy; however, its mechanism(s) of action are not fully understood. Objective: Here, we comprehensively investigated the role and changes of antigen-specific T cells before and after sublingual immunotherapy (SLIT) for Japanese cedar pollinosis (JCP). Methods: We cultured PBMCs obtained both before and at one-year after initiating SLIT and used a combination of single-cell RNA sequence and repertoire sequencing. To investigate biomarkers, we used PBMCs from patients participating a phase II/III trial of SLIT tablets for JCP and PBMCs from good and poor responders in outpatients. Results: Antigen-stimulated culturing after SLIT led to clonal expansion of Th2 and Treg cells, and most of these CD4+ T cells retained their CDR3 regions before and after treatment, indicating antigen-specific clonal responses and differentiation secondary to SLIT. However, SLIT reduced the number of clonal functional Th2 cells but increased the Trans-type Th2 cell population that expresses musculin (MSC), TGF-β, and IL-2. Trajectory analysis suggested that SLIT induced clonal differentiation of the Trans-type Th2 cells differentiated into Treg cells. By using real-time PCR, we found that MSC levels increased after 1 year of treatment in the active SLIT group and good responders. Conclusion: The combination of single-cell RNA sequencing and repertoire analysis helped reveal a part of the underlying mechanism— that SLIT promotes the expression of MSC on pathogenic Th2 cells and suppresses their function, and that MSC may be a potential biomarker of SLIT for allergic rhinitis. Clinical implications MSC expression was higher in the group of active patients who were responsive to SLIT, indicating that these molecules may be potential biomarkers of SLIT efficacy.
2022-04-07 | GSE200107 | GEO