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Distinct roles for IL-27 and IFN-g in the development of T-bet+ Treg required to limit infection-induced pathology

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE38686 | GEO | 2012/09/07

SECONDARY ACCESSION(S): PRJNA168438

REPOSITORIES: GEO

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Distinct roles for IL-27 and IFN-g in the development of T-bet+ Treg required to limit infection-induced pathology

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.

2012-09-07 | E-GEOD-38686 | biostudies-arrayexpress

IFNγ signaling endows DCs with the capacity to control type I inflammation during parasitic infection through promoting T-bet+ regulatory T cells

Project description:Transcriptome analysis of IFNγ-insensitive DCs IFNγ signaling drives dendritic cells (DCs) to promote type I T cell (Th1) immunity. Here, we show that activation of DCs by IFNγ is equally crucial for the differentiation of a population of T-bet+ regulatory T (Treg) cells specialized to inhibit Th1 immune responses. Conditional deletion of IFNγ receptor in DCs but not in Treg cells resulted in a severe defect in this specific Treg cell subset, leading to exacerbated immune pathology during parasitic infections. Mechanistically, IFNγ-unresponsive DCs failed to produce sufficient amount of IL-27, a cytokine required for optimal T-bet induction in Treg cells. Thus, IFNγ signalling endows DCs with the ability to efficiently control a specific type of T cell immunity through promoting a corresponding Treg cell population. We analyzed saliva from 3 WT DC samples and 3 IFNγR2 KO DC samples isolated from unmanipulated mice. In addition, we analyzed saliva from 3 WT DC samples and 3 IFNγR2 KO DC samples isolated from mixed BM chimeras (WT + IFNgR2KO) day 8 T. gondii infected.

2015-01-01 | E-GEOD-64594 | biostudies-arrayexpress

CXCR3+ Treg cells suppress Th1-immune responses through expression of the co-inhibitory receptors CD85k and Lag-3

Project description:CD4+Foxp3+ Treg cells are essential for maintaining self-tolerance and preventing excessive immune responses. In the context of Th1 immune responses, co-expression of the Th1 transcription factor T-bet with Foxp3 is essential for Treg cells to control Th1 responses. T-bet-dependent expression of CXCR3 directs Tregs to the site of inflammation, however, the suppressive mediators enabling effective control of Th1 responses at this site are unknown. In this study, we determined the signature of CXCR3+ Treg cells arising in Th1 settings and defined universal features of Treg cells in this context using multiple Th1-dominated models. Our analysis defined a set of Th1-specific co-inhibitory receptors that are specifically expressed in Treg cells during Th1 immune responses. Among these, we identified the novel co-inhibitory receptor CD85k as a functional mediator of the enhanced suppression of Th1 effector cells by CXCR3+ Treg cells.

2018-06-30 | E-MTAB-6156 | biostudies-arrayexpress

IFNγ signaling endows DCs with the capacity to control type I inflammation during parasitic infection through promoting T-bet+ regulatory T cells

2015-01-01 | GSE64594 | GEO

The distinct function and control of regulatory T cell subsets during influenza infection

Project description:During influenza infection, Treg cells in the lung acquire at least 3 discernable phenotypes which can be characterized by the expression of the IL-33 receptor ST2, the Th1 associated chemokine receptor CXCR3 or neither receptor. It is known in the Treg field that Treg cell acquire different phenotypes to more specifically target related immune responses. For example, Th1 like CXCR3 expressing Treg cells are thought to traffic to and specifically suppress adaptive type 1 immune responses. We have found that during influenza infection, ST2+ Treg cells specifically target innate immune responses characterized by IL-1 mediated neutrophil and eosinophil recruitment and the activation of IL17 producing gamma delta T cells. In order to determine how ST2+ Treg cell perform their specific immunomodulatory function, we have performed RNAseq transcriptomic analysis to compare gene expression in ST2+ Tregs isolated from day 7 influenza infected lungs with CXCR3+ Treg cells and Treg cells expressing neither marker also from day 7 of influenza infected lungs as well as compared to total Treg cells from the spleen of uninfected mice.

2022-03-31 | GSE173249 | GEO

Inflammation-dependent differentiation of two distinct regulatory T cell populations in the visceral adipose tissue shapes systemic metabolism [RNA-seq I]

Project description:Visceral adipose tissue (VAT) is an endocrine organ critical for energy storage and metabolic homeostasis. Its function, at least in part, is controlled by immune cells, including Foxp3+ regulatory T (Treg) cells, which restrain VAT inflammation and glucose intolerance. Here we uncover that the VAT harbours two distinct Treg cell populations, prototypical ST2+ Treg cells, that are enriched in males and depend on the cytokine IL-33 and the transcription factor PPAR and a previously uncharacterized population of VAT Treg cells that express the chemokine receptor CXCR3+, are enriched in females and depend on the transcription factor T-bet. We further show that the transcription factor GATA3 promoted differentiation of ST2+ VAT Treg cells and together with PPAR and IL-33 repressed the differentiation of CXCR3+ Treg cells. CXCR3+ VAT Treg cells developed from naïve Treg cells in a cytokine IFN- dependent manner. Finally, we demonstrate that ST2+ Treg cells promoted glucose tolerance, while CXCR3+ Treg cells limited VAT inflammation in a sex specific manner. This study for the first time establishes how inflammation determines the developmental trajectories of two functionally and molecularly distinct Treg cell types in the VAT.

2024-01-04 | GSE205427 | GEO

Inflammation-dependent differentiation of two distinct regulatory T cell populations in the visceral adipose tissue shapes systemic metabolism [RNA-seq III]

2024-03-22 | GSE237835 | GEO

Inflammation-dependent differentiation of two distinct regulatory T cell populations in the visceral adipose tissue shapes systemic metabolism [RNA-seq II]

2024-03-22 | GSE235420 | GEO

Excessive miR-27 expression impairs regulatory T cell-mediated immunological tolerance [Foxp3cre het miR-27Tg]

Project description:MicroRNAs (miRNAs) are tightly regulated in the immune system, as aberrant expression of miRNAs often results in hematopoietic malignancies and autoimmune diseases. Previously, elevated levels of miR-27 in T cells isolated from multiple sclerosis patients has been suggested to facilitate disease progression through inhibiting Th2 immunity and promoting pathogenic Th1 responses. Here we demonstrate that while mice with T cell-specific overexpression of miR-27 harbor dysregulated Th1 responses and develop autoimmune pathology, these disease phenotypes are not driven by miR-27 in effector T cells in a cell-autonomous manner but rather resulted from a perturbed regulatory T (Treg) cell compartment. Excessive miR-27 expression in T cells severely impairs Treg cell differentiation. Moreover, Treg cells with exaggerated miR-27-mediated gene regulation exhibit diminished homeostasis and suppressor function in vivo. Mechanistically, miR-27 represses several known as well as previously uncharacterized targets that play critical roles in controlling multiple aspects of Treg cell biology. Collectively, our data show miR-27 functions as a key regulator in Treg cell development and function and suggest that proper regulation of miR-27 is pivotal to safeguard Treg cell-mediated immunological tolerance.

2016-11-05 | GSE89547 | GEO

Excessive miR-27 expression impairs regulatory T cell-mediated immunological tolerance [CD4cre miR-23 clusterTg Tr]

2016-11-05 | GSE89546 | GEO

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