The Transcription Factor T-bet Limits Amplification of Type I IFN Transcriptome and Circuitry in T Helper 1 Cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE96724 | GEO | 2017/06/12
SECONDARY ACCESSION(S): PRJNA379464
REPOSITORIES: GEO
Similar Datasets
Project description:Type I interferons (IFNs) play an essential role in antiviral immunity, correlate with severity of systemic autoimmune disease, and are likely to represent a key component of mRNA vaccine-adjuvanticity. Relevant to all, type I IFNs can enhance germinal center (GC) B cell responses but underlying signaling pathways are incompletely understood due to pleiotropic effects in multiple cell types. Here, we demonstrate that a succinct type I IFN response promotes GC formation and associated IgG subclass distribution primarily through signaling in cDCs and B cells. Type I IFN signaling in cDCs, distinct from cDC1, stimulates development of separable Tfh and Th1 cell subsets. However, Th cell-derived IFN-g induces T-bet expression and IgG2c isotype switching prior to this bifurcation and has no evident effects once GCs and bona fide Tfh cells developed. This pathway acts in synergy with early B cell-intrinsic type I IFN signaling, which reinforces T-bet expression in B cells and leads to a selective amplification of the IgG2c+ GC B cell response. Despite the strong Th1 polarizing effect of type I IFNs, the Tfh cell subset develops into IL-4 producing cells that control the overall magnitude of the GCs and promote generation of IgG1+ GC B cells. Thus, type I IFNs act on B cells and cDCs to drive GC formation and to coordinate IgG subclass distribution through parallel Th1 and Tfh cell-dependent pathways.
2022-07-08 | GSE201551 | GEO
Project description:This a model from the article:
Sequential polarization and imprinting of type 1 T helper lymphocytes by interferon-gamma and interleukin-12.
Schulz EG, Mariani L, Radbruch A, Höfer T.
Immunity.2009;30(5):666-8.
19409816,
Abstract:
Differentiation of naive T lymphocytes into type I T helper (Th1) cells requires interferon-gamma and interleukin-12. It is puzzling that interferon-gamma induces the Th1 transcription factor T-bet, whereas interleukin-12 mediates Th1 cell lineage differentiation. We use mathematical modeling to analyze the expression kinetics of T-bet, interferon-gamma, and the IL-12 receptor beta2 chain (IL-12Rbeta2) during Th1 cell differentiation, in the presence or absence of interleukin-12 or interferon-gamma signaling. We show that interferon-gamma induced initial T-bet expression, whereas IL-12Rbeta2 was repressed by T cell receptor (TCR) signaling. The termination of TCR signaling permitted upregulation of IL-12Rbeta2 by T-bet and interleukin-12 signaling that maintained T-bet expression. This late expression of T-bet, accompanied by the upregulation of the transcription factors Runx3 and Hlx, was required to imprint the Th cell for interferon-gamma re-expression. Thus initial polarization and subsequent imprinting of Th1 cells are mediated by interlinked, sequentially acting positive feedback loops of TCR-interferon-gamma-Stat1-T-bet and interleukin-12-Stat4-T-bet signaling.
The original model was created by:
Edda G. Schulz
schulz@drfz.de
Theoretical Biophysics, Institute of Biology, Humboldt Universität, Invalidenstrasse 42, 10115 Berlin, Germany.
This model originates from BioModels Database: A Database of Annotated Published Models. It is copyright (c) 2005-2009 The BioModels Team.For more information see the terms of use.To cite BioModels Database, please use Le Novère N., Bornstein B., Broicher A., Courtot M., Donizelli M., Dharuri H., Li L., Sauro H., Schilstra M., Shapiro B., Snoep J.L., Hucka M. (2006) BioModels Database: A Free, Centralized Database of Curated, Published, Quantitative Kinetic Models of Biochemical and Cellular Systems Nucleic Acids Res., 34: D689-D691.
2024-09-02 | BIOMD0000000215 | BioModels
Project description:Given T-bet is a master regulator for Th1 differentiation that produce IFN-gamma, underlining mechanisms accounted for the distinct GVHD outcomes caused by T-bet- versus IFN-gamma-deficient donor T cells are unclear. We hypothesize that GVHD is regulated by T-bet-dependent but IFN-gamma-independent molecules. To identify these molecules, we isolated donor T cells from spleen cells of the recipients that were transplanted with WT, T-bet-/- or IFN-gamma-/- CD4 T cells for 7 days. The gene profile of isolated T cells was measured by microarray analysis using GeneChip Mouse Genome 430 2.0 arrays (Affymetrix) according to the manufacturerM-^Rs instructions. Array images were analyzed and processed by robust multi-array average (RMA) procedure.
2014-10-30 | E-MTAB-2198 | biostudies-arrayexpress
Project description:Type 1 T helper (Th1) cells play a critical role in host defense against intracellular pathogens and in autoimmune diseases by producing a key inflammatory cytokine interferon (IFN)-γ; some Th1 cells can also be anti-inflammatory through producing IL-10. However, the molecular switch for regulating the differentiation of inflammatory and anti-inflammatory Th1 cells is still elusive. Here we show that Bhlhe40-deficient CD4 Th1 cells produced less IFN-γ but substantially more IL-10 than wild type Th1 cells. Bhlhe40-mediated IFN-γ production was independent of transcription factor T-bet regulation. Mice with conditional deletion of Bhlhe40 in T cells succumbed to Toxoplasma gondii infection and blockage of IL-10 signaling during infection rescued these mice from death. Thus, our results demonstrate that transcription factor Bhlhe40 is a molecular switch for determining the fate of inflammatory and anti-inflammatory Th1 cells.
2018-05-10 | GSE103173 | GEO
Project description:Type-I (e.g. IFN-alpha, IFN-beta) and type-II IFNs (IFN-gamma) have antiviral, antiproliferative, and immunomodulatory properties. Both types of IFN signal through the Jak/STAT pathway to elicit antiviral activity, yet IFN-gamma is thought to do so only through STAT1 homodimers while type-I IFNs activate both STAT1- and STAT2-containing complexes such as ISGF3. Here we show that ISGF3II - composed of phosphorylated STAT1, unphosphorylated STAT2, and IRF9 - also plays a role in IFN-gamma-mediated antiviral activity in humans. Using phosphorylated STAT1 as a marker for IFN signaling, western blot analysis of IFN-alpha2a treated human A549 cells revealed that pSTAT1 (Y701) levels peaked at 1h, decreased by 6h, and remained at low levels for up to 48h. Cells treated with IFN-gamma showed a biphasic pSTAT1 response with an early peak at 1-2h and a second peak at 15-24h. Gene expression microarray following IFN-gamma treatment for 24h indicated an induction of antiviral genes that are induced by ISGF3 and associated with a type-1 IFN response. Induction of these genes by autocrine type-I and type-III IFN signaling was ruled out using neutralizing antibodies to these IFNs in biological assays and by qRT-PCR. Despite the absence of autocrine IFNs, IFN-gamma treatment induced formation of ISGF3II. This novel transcription factor complex binds to ISRE promoter sequences, as shown by ChIP analysis of the PKR promoter. STAT2 and IRF9 knockdown in A549 cells reversed IFN-gamma-mediated ISRE induction and antiviral activity - implicating ISGF3II formation as a significant component of the cellular response and biological activity of IFN-gamma. Two treatments using three biological replicates each were performed using three million A549 cells. Each was seeded overnight in 10mL complete RPMI and treated. Three were treated with alpha-IFN and three treated with gamma-IFN for 24h. Control samples were left untreated.
2011-01-19 | E-GEOD-25113 | biostudies-arrayexpress
Project description:Type-I (e.g. IFN-alpha, IFN-beta) and type-II IFNs (IFN-gamma) have antiviral, antiproliferative, and immunomodulatory properties. Both types of IFN signal through the Jak/STAT pathway to elicit antiviral activity, yet IFN-gamma is thought to do so only through STAT1 homodimers while type-I IFNs activate both STAT1- and STAT2-containing complexes such as ISGF3. Here we show that ISGF3II - composed of phosphorylated STAT1, unphosphorylated STAT2, and IRF9 - also plays a role in IFN-gamma-mediated antiviral activity in humans. Using phosphorylated STAT1 as a marker for IFN signaling, western blot analysis of IFN-alpha2a treated human A549 cells revealed that pSTAT1 (Y701) levels peaked at 1h, decreased by 6h, and remained at low levels for up to 48h. Cells treated with IFN-gamma showed a biphasic pSTAT1 response with an early peak at 1-2h and a second peak at 15-24h. Gene expression microarray following IFN-gamma treatment for 24h indicated an induction of antiviral genes that are induced by ISGF3 and associated with a type-1 IFN response. Induction of these genes by autocrine type-I and type-III IFN signaling was ruled out using neutralizing antibodies to these IFNs in biological assays and by qRT-PCR. Despite the absence of autocrine IFNs, IFN-gamma treatment induced formation of ISGF3II. This novel transcription factor complex binds to ISRE promoter sequences, as shown by ChIP analysis of the PKR promoter. STAT2 and IRF9 knockdown in A549 cells reversed IFN-gamma-mediated ISRE induction and antiviral activity - implicating ISGF3II formation as a significant component of the cellular response and biological activity of IFN-gamma.
2011-01-19 | GSE25113 | GEO
Project description:Experimental autoimmune encephalomyelitis (EAE) is the most widely used rodent model for multiple sclerosis. Interferon-γ (IFN-γ) and regulatory T cells (Tregs) are individually well known to play beneficial roles in amelioration of EAE. However, little is known about the relationship between IFN-γ and Tregs during the disease. Here we show that IFN-γ polarizes Tregs into Th1-type Tregs (Th1-Tregs) to recover from EAE. Single-cell RNA sequencing analysis revealed that brain Tregs showed signs of IFN-γ stimulation during EAE. Loss of IFN-γ signaling in Tregs and of T cell-derived IFN-γ impaired the Th1-Treg polarization and worsened the disease. Moreover, selective ablation of Th1-Tregs using an intersectional genetic method promoted pro-inflammatory features of macrophages in the inflamed brains and exacerbated the EAE. Taken together, our study highlights a critical role of T cell-derived IFN-γ for Th1-Treg polarization in inflamed brain to ameliorate EAE.
2024-11-06 | GSE254051 | GEO
Project description:Experimental autoimmune encephalomyelitis (EAE) is the most widely used rodent model for multiple sclerosis. Interferon-γ (IFN-γ) and regulatory T cells (Tregs) are individually well known to play beneficial roles in amelioration of EAE. However, little is known about the relationship between IFN-γ and Tregs during the disease. Here we show that IFN-γ polarizes Tregs into Th1-type Tregs (Th1-Tregs) to recover from EAE. Single-cell RNA sequencing analysis revealed that brain Tregs showed signs of IFN-γ stimulation during EAE. Loss of IFN-γ signaling in Tregs and of T cell-derived IFN-γ impaired the Th1-Treg polarization and worsened the disease. Moreover, selective ablation of Th1-Tregs using an intersectional genetic method promoted pro-inflammatory features of macrophages in the inflamed brains and exacerbated the EAE. Taken together, our study highlights a critical role of T cell-derived IFN-γ for Th1-Treg polarization in inflamed brain to ameliorate EAE.
2024-11-06 | GSE254050 | GEO
Project description:T-bet is a critical transcription factor for T helper 1 (Th1) cell differentiation. To study the regulation and functions of T-bet, we developed a T-bet-ZsGreen reporter mouse strain, in which GFP faithfully reflects the expression of T-bet. By using this tool, we report that signals elicited by IL-12 and IFNg are redundant in inducing T-bet in mice infected with Toxoplasma gondii and that T-bet does not contribute to its own expression when induced by IL-12 and IFNg. While both T-bet and Stat4 are critical for IFNg production, IFNg signaling is dispensable. Strikingly, loss of T-bet results in activation of an endogenous Th2 program in cells expressing T-bet-ZsGreen. Genome-wide analyses suggest T-bet directly induces Th1-related genes but indirectly suppresses Th2-related genes. Our study revealed redundancy and synergy among several Th1-inducing pathways in regulating the expression of T-bet and IFNg, and a critical role of T-bet in suppressing an endogenous Th2 program. RNA-Seq experiments were performed using total RNAs isolated from both wild type and Tbx21-/- Th1 cells in duplicates. Tbet ChIP-seq was performed using wild type Th1 cells. H3K4me1 and H3K27me3 ChIP-seq was performed using both wild type and Tbx21-/- Th1 cells.
2012-10-04 | E-GEOD-38808 | biostudies-arrayexpress
Project description:Tuberculosis, a chronic granulomatous disease caused by Mycobacterium tuberculosis (Mtb), often becomes exacerbated upon co-infection with other pathogens, yet the underlying immunological mechanisms remain insufficiently understood. Here, mice were initially infected with the hypervirulent Mtb strain K, and later with lymphocytic choriomeningitis virus to investigate the mechanism of severe pulmonary pathology. Virus infection significantly reduced Mtb-specific IFN-g, increased bacterial loads, and aggravated lung inflammation in the lung of Mtb-infected mice, which did not occur in pre-existence of Th1 response by Bacillus Calmette-Guerin vaccination prior to the co-infection. Blockade of type I IFN receptor signaling reinvigorated Mtb-specific IFN-γ response and ameliorated pathogenesis by upregulating pulmonary CXCL9/10 production. Our results demonstrate that virus-induced type I IFN triggers severe immunopathology by deteriorating migration of Mtb-specific IFN-γ-producing T cells, suggesting the balance between type I and type II IFNs determines either control of Mtb or exacerbation of pathology in the lung upon viral infection
2021-02-27 | GSE167650 | GEO