Treg-Derived IFN-γ Supports the Differentiation of Th1-Treg in tumor immunity and autoimmunity
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE327115 | GEO | 2026/06/03
REPOSITORIES: GEO
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Project description:The tumor microenvironment (TME) contains various immune-suppressive cells such as T helper 1-polarized regulatory T cells (Th1-Tregs). However, little is known about the mechanism behind the abundant presence of Th1-Tregs in TME. In this work, we demonstrate that selective depletion of arginase I (Arg1)-expressing tumor associated macrophages (Arg1+ TAMs) inhibits tumor growth and concurrently reduces the Th1-Treg ratio in TME. Notably, Arg1+ TAMs secrete platelet factor 4 (PF4) that reinforces interferon-γ (IFN-γ)-induced Treg polarization into Th1-Tregs in a manner dependent on CXCR3 and the IFN-γ receptor. Both genetic PF4 inactivation and PF4 neutralization hinder Th1-Treg accumulation in TME, consequently suppressing tumor growth. Collectively, our study highlights the importance of Arg1+ TAM-produced PF4 for high Th1-Treg levels in TME to suppress anti-tumor immunity, and demonstrates PF4 neutralization as a potential cancer immunotherapeutic strategy.
2024-11-07 | GSE252052 | GEO
Project description:The tumor microenvironment (TME) contains various immune-suppressive cells such as regulatory T cells (Tregs) and M2-like tumor associated macrophages (TAMs) that express the enzyme arginase I (Arg1). T helper 1-polarized Treg (Th1-Treg) is a Treg subset that markedly accumulate in tumor tissues, suppressing anti-tumor immunity. However, little is known about the mechanism behind the abundant presence of Th1-Tregs in TME. Here we show that Arg1-expressing TAMs (Arg1+ TAMs) play critical roles for the high Th1-Treg ratio in TME. Selective depletion of Arg1+ TAMs using the VeDTR system inhibited tumor growth and concurrently reduced the Th1-Treg ratio in TME. Notably, Arg1+ TAMs secreted platelet factor 4 (PF4) that polarized Tregs to Th1-Tregs in a CXCR3-dependent manner. Both genetic PF4 inactivation and PF4 neutralization hindered Th1-Treg accumulation in TME, consequently suppressing tumor growth. Collectively, our study highlights the importance of M2-like TAM-produced PF4 for high Th1-Treg levels in TME to suppress anti-tumor immunity, and demonstrates PF4 neutralization as a potential cancer immunotherapeutic strategy by intervening the M2-like TAM/Th1-Treg axis.
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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.
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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.
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Project description:IL-27 is a potent antagonist of TH1-mediated inflammation, but the basis for this effect is not fully understood. Recent studies identified a population of T-bet+ CXCR3+ Treg that limit TH1-mediated immune pathology. The studies presented here demonstrate that IL-27-mediated STAT1 activation promotes Treg expression of T-bet and CXCR3. Infection with Toxoplasma gondii induced a similar Treg population that limits T cell responses and this population at mucosal sites is IL-27-dependent. Furthermore, transfer of Treg ameliorated the infection-induced CD4+ T cell-mediated pathology observed in IL-27p28-/- mice. Although IFN-γ promoted a similar population of cells in the periphery, it did not compensate for the absence of IL-27 at mucosal sites and microarray analysis revealed that Treg exposed to either cytokine have distinct transcriptional profiles. These findings suggest that IFN-γ and IL-27 have different roles in Treg biology but define IL-27 as a key cytokine that promotes the development of Treg specialized to control TH1 immunity. Three conditions were analyzed across two timepoints. Inducible regulatory T cells (iTreg) were generated in vitro in the presence of IL-27, IFNg or under 'Neutral' conditions as a control. Samples were collected at 10 hours and 2 days during the culture period. Three biological replicates were used for each condition.
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Project description:Regulatory T cell (Treg) stability is maintained by dynamic remodeling of the FOXP3 transcriptional complex, and its disruption leads to Treg dysfunction and immune dysregulation. However, how specific FOXP3 mutations alter the dynamic remodeling of the FOXP3-complex and thereby contribute to pathogenic Treg reprogramming in IPEX syndrome remains unclear. Here, by uncovering the distinctive pathogenesis of FOXP3V408M mutation in IPEX syndrome, we demonstrate that the FOXP3–T-bet interaction fine-tunes Treg function by repressing IFN-γ production, thereby preventing Th1-driven inflammation. Using an AI-driven virtual screening approach, we identified a first-in-class small molecule, 430C10, that directly binds FOXP3 and reinforces its interaction with T-bet. 430C10 robustly suppressed Treg-derived IFN-γ production and alleviated IFN-γ-driven tissue inflammation in FOXP3V408M knock-in mice as well as in models of acute colitis. Collectively, these findings establish the FOXP3–T-bet interaction as a central checkpoint governing Treg stability and IFN-γ-driven Th1 pathology, providing proof-of-concept that pharmacologic stabilization of FOXP3–T-bet interaction can mitigate IFN-γ–driven immune disorders.
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Project description:Regulatory T cell (Treg) stability is maintained by dynamic remodeling of the FOXP3 transcriptional complex, and its disruption leads to Treg dysfunction and immune dysregulation. However, how specific FOXP3 mutations alter the dynamic remodeling of the FOXP3-complex and thereby contribute to pathogenic Treg reprogramming in IPEX syndrome remains unclear. Here, by uncovering the distinctive pathogenesis of FOXP3V408M mutation in IPEX syndrome, we demonstrate that the FOXP3–T-bet interaction fine-tunes Treg function by repressing IFN-γ production, thereby preventing Th1-driven inflammation. Using an AI-driven virtual screening approach, we identified a first-in-class small molecule, 430C10, that directly binds FOXP3 and reinforces its interaction with T-bet. 430C10 robustly suppressed Treg-derived IFN-γ production and alleviated IFN-γ-driven tissue inflammation in FOXP3V408M knock-in mice as well as in models of acute colitis. Collectively, these findings establish the FOXP3–T-bet interaction as a central checkpoint governing Treg stability and IFN-γ-driven Th1 pathology, providing proof-of-concept that pharmacologic stabilization of FOXP3–T-bet interaction can mitigate IFN-γ–driven immune disorders.
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Project description:Regulatory T cell (Treg) stability is maintained by dynamic remodeling of the FOXP3 transcriptional complex, and its disruption leads to Treg dysfunction and immune dysregulation. However, how specific FOXP3 mutations alter the dynamic remodeling of the FOXP3-complex and thereby contribute to pathogenic Treg reprogramming in IPEX syndrome remains unclear. Here, by uncovering the distinctive pathogenesis of FOXP3V408M mutation in IPEX syndrome, we demonstrate that the FOXP3–T-bet interaction fine-tunes Treg function by repressing IFN-γ production, thereby preventing Th1-driven inflammation. Using an AI-driven virtual screening approach, we identified a first-in-class small molecule, 430C10, that directly binds FOXP3 and reinforces its interaction with T-bet. 430C10 robustly suppressed Treg-derived IFN-γ production and alleviated IFN-γ-driven tissue inflammation in FOXP3V408M knock-in mice as well as in models of acute colitis. Collectively, these findings establish the FOXP3–T-bet interaction as a central checkpoint governing Treg stability and IFN-γ-driven Th1 pathology, providing proof-of-concept that pharmacologic stabilization of FOXP3–T-bet interaction can mitigate IFN-γ–driven immune disorders.
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