GITR subverts Foxp3+ Tregs to boost Th9 immunity through regulation of histone acetylation

Glucocorticoid-induced TNFR-related protein (GITR) is a costimulatory molecule with diverse effects on effector T cells and regulatory T cells (Tregs), but the underlying mechanism remains poorly defined. Here we demonstrate that GITR ligation subverts the induction of Foxp3+ Tregs and directs the activated CD4+ T cells to Th9 cells. Such GITR-mediated iTreg to Th9 induction enhances anti-tumour immunity in vivo. Mechanistically, GITR upregulates the NF-κB family member p50, which recruits histone deacetylases to the Foxp3 locus to produce a ‘closed’ chromatin structure. Furthermore, GITR ligation also activates STAT6, and STAT6 renders Il9 locus accessible via recruitment of histone acetyltransferase p300, and together with inhibition of Foxp3, GITR induces strong Th9 responses. Thus, Th9 cells and iTregs are developmentally linked and GITR can subvert tolerogenic conditions to boost Th9 immunity. Glucocorticoid-induced TNFR-related protein (GITR), a costimulatory protein expressed by T cells, has immunostimulatory effect but the underlying mechanism is not clear. Here the authors show that GITR ligation inhibits the induction of Foxp3 expression and diverts CD4 T cells towards Th9 differentiation instead of iTreg.

• Publication year

  2015

• Venue

  Nature Communications

• Publication date

  2015-09-14

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1038/ncomms9266PMID 26365427PMCID 4570275
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Regulatory T cells in cancer immunotherapy

  2016cited by this paper
• The transcription factor IRF1 dictates the IL-21-dependent anticancer functions of TH9 cells

  2014cited by this paper
• Phenotype and functions of memory Tfh cells in human blood.

  2014cited by this paper
• Complex interactions of transcription factors in mediating cytokine biology in T cells

  2014cited by this paper
• Regulatory T cells in cancer immunotherapy.

  2014cited by this paper
• Th9 cells, new players in adaptive immunity.

  2014cited by this paper
• Cell-specific and context-dependent effects of GITR in cancer, autoimmunity, and infection.

  2014cited by this paper
• Smad2/3 and IRF4 Play a Cooperative Role in IL-9-Producing T Cell Induction(審査報告)

  2014cited by this paper
• TH9 cells that express the transcription factor PU.1 drive T cell–mediated colitis via IL-9 receptor signaling in intestinal epithelial cells

  2014cited by this paper
• IL-9 Regulates Allergen-Specific Th1 Responses in Allergic Contact Dermatitis

  2014cited by this paper
• Development and maintenance of regulatory T cells.

  2013cited by this paper
• Smad2/3 and IRF4 Play a Cooperative Role in IL-9–Producing T Cell Induction

  2013cited by this paper
• Th9 Cells Drive Host Immunity against Gastrointestinal Worm Infection.

  2013cited by this paper
• Th9 cells: differentiation and disease

  2013cited by this paper
• Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells

  2013cited by this paper
• Epigenetic control of cytokine gene expression: regulation of the TNF/LT locus and T helper cell differentiation.

  2013cited by this paper
• Interleukin-9 is required for allergic airway inflammation mediated by the cytokine TSLP.

  2013cited by this paper
• IL-9 and Th9 cells: progress and challenges.

  2013cited by this paper
• Th9 cell development requires a BATF-regulated transcriptional network.

  2013cited by this paper
• Transcriptional control of regulatory T-cell differentiation.

  2013cited by this paper
• STAT6-Dependent Regulation of Th9 Development

  2012cited by this paper
• Notch receptors and Smad3 signaling cooperate in the induction of interleukin-9-producing T cells.

  2012cited by this paper
• Transcription factor Foxp3 and its protein partners form a complex regulatory network

  2012cited by this paper
• Th9 cells promote antitumor immune responses in vivo.

  2012cited by this paper
• Extrathymically generated regulatory T cells control mucosal TH2 inflammation

  2012cited by this paper
• Robust tumor immunity to melanoma mediated by interleukin 9

  2012cited by this paper
• OX40 signaling favors the induction of TH9 cells and airway inflammation

  2012cited by this paper
• Interleukin 9 fate reporter reveals induction of innate IL-9 response in lung inflammation

  2011cited by this paper
• Crosstalk in NF-κB signaling pathways

  2011cited by this paper
• The transcription factor PU.1 is required for the development of interleukin 9-producing T cells and allergic inflammation

  2010cited by this paper
• Cellular sources and immune functions of interleukin-9

  2010cited by this paper
• Interferon-regulatory factor 4 is essential for the developmental program of T helper 9 cells.

  2010cited by this paper
• Anti-GITR antibodies--potential clinical applications for tumor immunotherapy.

  2010cited by this paper
• Faculty Opinions recommendation of The transcription factor PU.1 is required for the development of IL-9-producing T cells and allergic inflammation.

  2010cited by this paper
• Instability of the transcription factor Foxp3 leads to the generation of pathogenic memory T cells in vivo

  2009cited by this paper
• IL-9 as a mediator of Th17-driven inflammatory disease

  2009cited by this paper
• Regulation and function of NF-kappaB transcription factors in the immune system.

  2009cited by this paper
• Development of Foxp3(+) regulatory t cells is driven by the c-Rel enhanceosome.

  2009cited by this paper
• Novel aminophenyl benzamide-type histone deacetylase inhibitors with enhanced potency and selectivity.

  2007cited by this paper
• OX40 costimulation turns off Foxp3+ Tregs.

  2007cited by this paper
• Activation-induced FOXP3 in human T effector cells does not suppress proliferation or cytokine production.

  2007cited by this paper
• Contrasting Effects of Cyclosporine and Rapamycin in De Novo Generation of Alloantigen‐Specific Regulatory T Cells

  2007cited by this paper
• Foxp3-dependent programme of regulatory T-cell differentiation

  2007cited by this paper
• The GITR–GITRL interaction: co-stimulation or contrasuppression of regulatory activity?

  2006cited by this paper
• Mast cells are essential intermediaries in regulatory T-cell tolerance

  2006cited by this paper
• Diversification of T-helper-cell lineages: finding the family root of IL-17-producing cells

  2006cited by this paper
• SIRT1 Modulating Compounds from High-Throughput Screening as Anti-Inflammatory and Insulin-Sensitizing Agents

  2006cited by this paper
• TNF/TNFR family members in costimulation of T cell responses.

  2005cited by this paper
• Trichostatin A-like hydroxamate histone deacetylase inhibitors as therapeutic agents: toxicological point of view.

  2004cited by this paper
• Modulation of NF‐κB‐dependent transcription and cell survival by the SIRT1 deacetylase

  2004cited by this paper
• The Phosphorylation Status of Nuclear NF-ΚB Determines Its Association with CBP/p300 or HDAC-1

  2002cited by this paper
• The phosphorylation status of nuclear NF-kappa B determines its association with CBP/p300 or HDAC-1.

  2002cited by this paper
• Mice Deficient in Nuclear Factor (NF)-κB/p52 Present with Defects in Humoral Responses, Germinal Center Reactions, and Splenic Microarchitecture

  1998cited by this paper
• Targeted disruption of the p50 subunit of NF-kappa B leads to multifocal defects in immune responses.

  1995cited by this paper
• Targeted disruption of the p50 subunit of NF-κB leads to multifocal defects in immune responses

  1995cited by this paper
• The effect of sodium butyrate on histone modification.

  1978cited by this paper

• Molecular requirements of pathogenic Th2 cell differentiation in allergic airway disease.

  2026cites this paper
• GITRL enhances cytotoxicity and persistence of CAR-T cells in cancer therapy.

  2025cites this paper
• Th9 cells provide protective TB immunity

  2025influential citation
• NF-κB in inflammation and cancer

  2025cites this paper
• Three's company: The cooperative signals behind the differentiation of Th9 cells.

  2025cites this paper
• Progress and Future Perspectives of Treg Cell Therapy.

  2025cites this paper
• Tissue‐Resident Regulatory T Cells Expressing CD83 Maintain Local Homeostasis and Restrict Th2 Responses in Asthma

  2025cites this paper
• ACC1 is a dual metabolic-epigenetic regulator of Treg stability and immune tolerance

  2025cites this paper
• TL1A/DR3 signaling regulates the generation of pathogenic Th9 cells in experimental Crohn's disease.

  2025cites this paper
• The NF-κB signaling network in the life of T cells

  2025cites this paper
• A systems immunology perspective on gout pathogenesis and its precision-targeted treatment strategies

  2025cites this paper
• Sphingosylphosphorylcholine Promotes Th9 Cell Differentiation Through Regulation of Smad3, STAT5, and β-Catenin Pathways

  2024cites this paper
• GITR exacerbates lysophosphatidylcholine-induced macrophage pyroptosis in sepsis via posttranslational regulation of NLRP3

  2024cites this paper
• Treg Cell Therapeutic Strategies for Breast Cancer: Holistic to Local Aspects

  2024cites this paper
• Emerging Roles of Adaptive Immune Response in Alzheimer's Disease

  2024cites this paper
• TL1A priming induces a multi-cytokine Th9 cell phenotype that promotes robust allergic inflammation in murine models of asthma

  2024cites this paper
• The Role of Immune Cells in the Pathogenesis of Idiopathic Pulmonary Fibrosis

  2023cites this paper
• The Dichotomy of Interleukin-9 Function in the Tumor Microenvironment

  2023cites this paper
• Interplay between epigenetic and genetic alterations in inborn errors of immunity.

  2023cites this paper
• Model‐informed drug development for immuno‐oncology agonistic anti‐GITR antibody GWN323: Dose selection based on MABEL and biologically active dose

  2022cites this paper
• IL-1β promotes IL-9-producing Th cell differentiation in IL-2-limiting conditions through the inhibition of BCL6

  2022cites this paper
• Neuroinflammation: Extinguishing a blaze of T cells

  2022cites this paper
• Intratracheal administration of mesenchymal stem cells modulates lung macrophage polarization and exerts anti-asthmatic effects

  2022cites this paper
• IL-9 Producing Tumor-Infiltrating Lymphocytes and Treg Subsets Drive Immune Escape of Tumor Cells in Non-Small Cell Lung Cancer

  2022cites this paper
• Pathogen size alters C-type lectin receptor signaling in dendritic cells to influence CD4 Th9 cell differentiation

  2022cites this paper
• The Importance of the Transcription Factor Foxp3 in the Development of Primary Immunodeficiencies

  2022cites this paper
• Lysine Acetylation, Cancer Hallmarks and Emerging Onco-Therapeutic Opportunities

  2022influential citation
• Optimal target saturation of ligand-blocking anti-GITR antibody IBI37G5 dictates FcγR-independent GITR agonism and antitumor activity

  2022cites this paper
• Triple-modality therapy maximizes antitumor immune responses in a mouse model of mesothelioma

  2021cites this paper
• Critical Roles of Balanced T Helper 9 Cells and Regulatory T Cells in Allergic Airway Inflammation and Tumor Immunity

  2021influential citation
• The many-sided contributions of NF-κB to T-cell biology in health and disease.

  2021cites this paper
• GITR Promotes the Polarization of TFH-Like Cells in Helicobacter pylori-Positive Gastritis

  2021cites this paper
• IL-4 inhibits regulatory T cells differentiation by HDAC9-mediated epigenetic regulation

  2021cites this paper
• Harnessing TH9 cells in cancer immunotherapy.

  2021cites this paper
• Epimedin C modulates the balance between Th9 cells and Treg cells through negative regulation of noncanonical NF-κB pathway and MAPKs activation to inhibit airway inflammation in the ovalbumin-induced murine asthma model.

  2021cites this paper
• STAT6 Pathway Is Critical for the Induction and Function of Regulatory T Cells Induced by Mucosal B Cells

  2021cites this paper
• IL-9 and Th9 Cells in Tumor Immunity.

  2020cites this paper
• The emerging role of co-stimulatory molecules and their agonistic mAb-based combination therapies in melanoma.

  2020cites this paper
• In-Vitro Inhibition of P38 Abrogates GITR-Induced Proliferation of Murine iTregs

  2020cites this paper
• STAT5 promotes accessibility and is required for BATF-mediated plasticity at the Il9 locus

  2020cites this paper
• Revisiting the role of CD4+ T cells in cancer immunotherapy—new insights into old paradigms

  2020cites this paper
• The outstanding antitumor capacity of CD4+ T helper lymphocytes.

  2020cites this paper
• Tumor Microenvironment: The Role of Interleukins – Part A

  2020cites this paper
• Calcitriol Regulates the Differentiation of IL-9–Secreting Th9 Cells by Modulating the Transcription Factor PU.1

  2020influential citation
• Epigenetic conversion of conventional T cells into regulatory T cells by CD28 signal deprivation

  2020cites this paper
• Epigenetically modifying the Foxp3 locus for generation of stable antigen‐specific Tregs as cellular therapeutics

  2020cites this paper
• Th9 Cell Differentiation and Its Dual Effects in Tumor Development

  2020cites this paper
• Combined chemotherapy of platinum and fluorouracil promotes T cell-mediated antitumor immunity.

  2020cites this paper
• Th9 Cells in Allergic Disease

  2019cites this paper
• Features and roles of T helper 9 cells and interleukin 9 in immunological diseases.

  2019cites this paper
• Butyrate Attenuates Lung Inflammation by Negatively Modulating Th9 Cells

  2019cites this paper
• GM-CSF Promotes Antitumor Immunity by Inducing Th9 Cell Responses

  2019cites this paper
• Transcriptional and epigenetic regulation of immune tolerance: roles of the NF-κB family members

  2019cites this paper
• IL-4 together with IL-1β induces antitumor Th9 cell differentiation in the absence of TGF-β signaling

  2019cites this paper
• Skin‐homing T‐cell responses associated with Demodex infestation and rosacea

  2019cites this paper
• Expression of costimulatory and inhibitory receptors in FoxP3+ regulatory T cells within the tumor microenvironment: Implications for combination immunotherapy approaches.

  2019cites this paper
• The dichotomous function of interleukin-9 in cancer diseases

  2019cites this paper
• Emerging Roles of Th9 Cells as an Anti-tumor Helper T Cells

  2019cites this paper
• T Helper 9 Cells: A New Player in Immune-Related Diseases

  2019cites this paper
• Role of NF-kappaB2-p100 in regulatory T cell homeostasis and activation

  2019cites this paper
• Th9 cytokines curb cervical cancer progression and immune evasion.

  2019cites this paper
• NEDD4 Negatively Regulates GITR via Ubiquitination in Immune Microenvironment of Melanoma

  2019cites this paper
• OTT_A_212317 10629..10637

  2019cites this paper
• Étude du rôle du TGF-β dans la différenciation mémoire des lymphocytes T et son implication potentielle pour l'immunothérapie adoptive

  2019influential citation
• Structure-Function Analysis of Immune Checkpoint Receptors to Guide Emerging Anticancer Immunotherapy.

  2018cites this paper
• TGF-β in T Cell Biology: Implications for Cancer Immunotherapy

  2018cites this paper
• Controlled release of an HDAC inhibitor for reduction of inflammation in dry eye disease.

  2018cites this paper
• Guidance of super-enhancers in regulation of IL-9 induction and airway inflammation

  2018influential citation
• Transcriptional Control of Th9 Cells: Role of Foxo1 in Interleukin-9 Induction

  2018cites this paper
• Decreased frequency of circulating Th9 cells in patients with chronic hepatitis B infection

  2018cites this paper
• Physiological low-dose oestrogen promotes the development of experimental autoimmune thyroiditis through the up-regulation of Th1/Th17 responses.

  2018cites this paper
• Proteomic Analyses of Human Regulatory T Cells Reveal Adaptations in Signaling Pathways that Protect Cellular Identity

  2018cites this paper
• CD96 expression determines the inflammatory potential of IL-9–producing Th9 cells

  2018cites this paper
• FRI0158 Prostaglandin e2 and its receptor subtype ep4 are involved in ankylosing spondylitis disease progression

  2018cites this paper
• FRI0160 Interleukin-17a induces inflammatory response via nlrp3 inflammasome in ankylosing spondylitis

  2018cites this paper
• Tumor Necrosis Factor Receptor Superfamily in T Cell Priming and Effector Function.

  2018cites this paper
• [Expression of interleukin-9 in colon cancer tissues and its clinical significance].

  2018cites this paper
• Glucocorticoid-induced TNFR-related gene (GITR) as a therapeutic target for immunotherapy

  2018cites this paper
• OX40 Costimulation Inhibits Foxp3 Expression and Treg Induction via BATF3-Dependent and Independent Mechanisms.

  2018cites this paper
• The interplay between genetic and environmental factors in the pathogenesis of atopic dermatitis

  2017cites this paper
• Trial Watch: Immunostimulatory monoclonal antibodies for oncological indications

  2017cites this paper
• GITR: A Modulator of Regulatory and Effector T‐Cell Activity, Crucial in Tumour Rejection and Autoimmune Diseases

  2017cites this paper
• IL-36γ signaling controls the induced regulatory T cell – TH9 cell balance via NFκB activation and STAT transcription factors

  2017cites this paper
• DNMT1 cooperates with MBD4 to inhibit the expression of Glucocorticoid‐induced TNFR‐related protein in human T cells

  2017cites this paper
• Chemokine-Driven CD4+ T Cell Homing: New Concepts and Recent Advances.

  2017cites this paper
• Reciprocal regulation of the Il9 locus by counteracting activities of transcription factors IRF1 and IRF4

  2017cites this paper
• IL-9 and Th9 cells in health and diseases-From tolerance to immunopathology.

  2017cites this paper
• Foxo1 and Foxp1 play opposing roles in regulating the differentiation and antitumor activity of TH9 cells programmed by IL-7

  2017cites this paper
• Forkhead box protein‐3 (Foxp3)‐producing dendritic cells suppress allergic response

  2017cites this paper
• Nocardia rubra cell-wall skeleton promotes CD4+ T cell activation and drives Th1 immune response.

  2017cites this paper
• Th9 Cells: New Member of T Helper Cell Family.

  2017cites this paper
• Elevated levels of Bcl-3 inhibits Treg development and function resulting in spontaneous colitis

  2017cites this paper
• The Differentiation and Function of Th2 and Th9 Cells

  2016cites this paper
• Cottrell atmospheres along dislocations in long-period stacking ordered phases in a Mg–Zn–Y alloy

  2016cites this paper
• TH9 cells in anti-tumor immunity

  2016influential citation
• Phenotypical characterization of regulatory T cells in humans and rodents

  2016cites this paper
• Alkaline Cytosolic pH and High Sodium Hydrogen Exchanger 1 (NHE1) Activity in Th9 Cells*

  2016cites this paper
• Involvement of NHE 1 in Th 9 cells development and function 1 Alkaline Cytosolic pH and High Sodium Hydrogen Exchanger 1 ( NHE 1 ) Activity in Th 9 cells

  2016cites this paper
• The transcription factor network in Th9 cells

  2016influential citation
• Graft‐Infiltrating Macrophages Adopt an M2 Phenotype and Are Inhibited by Purinergic Receptor P2X7 Antagonist in Chronic Rejection

  2016cites this paper