Functional Plasticity of Regulatory T Cell Function
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE29262 | GEO | 2011/12/08
SECONDARY ACCESSION(S): PRJNA140267
REPOSITORIES: GEO
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Project description:Regulatory T cells (Tregs) can suppress a wide variety of cell types, in diverse organ sites and inflammatory conditions. While Tregs possess multiple suppressive mechanisms, the number required for maximal function is unclear. Furthermore, whether any inter-relationship orcross-regulatory mechanisms exist that areused to orchestrate and control their utilization is unknown. Here we assessed the functional capacity of Tregs lacking the ability to secrete both interleukin-10 (IL-10) and IL-35, which individually are required for maximal Treg activity. Surprisingly, IL-10/IL-35-double deficient Tregswere fully functionalin vitro and in vivo. Loss of IL-10 and IL-35 was compensated for by a concurrent increase in cathepsin E (CTSE) expression, enhanced TRAIL (Tnfsf10)expression and soluble TRAIL release, rendering IL-10/IL-35-double deficient Tregsfunctionally dependent on TRAIL in vitro and in vivo. Lastly, while C57BL/6 Tregs are IL-10/IL-35-dependent, Balb/c Tregs, which express high levels of CTSE and enhanced TRAIL expression, are TRAIL-dependent.These data reveal that cross-regulatory pathways exist, which control the utilization of suppressive mechanisms,thereby providing Tregfunctional plasticity. Isolate natural Tregs from the different knockout mouse
2011-12-08 | E-GEOD-29262 | biostudies-arrayexpress
Project description:Foxp3 expressing regulatory T cells (Tregs) are the central regulator of immune homeostasis and tolerance. As it is believed that proper Treg function is compromised under inflammatory conditions, exploring a pathway that enhances Treg function is of great importance. In this study, we report that IL-27, an IL-12 family cytokine known to play both pro- and anti-inflammatory role in T cells, plays a pivotal role in Treg function to control T cell-induced colitis. Unlike WT Tregs capable of inhibiting colitogenic T cell expansion and inflammatory cytokine expression, IL-27R-deficient Tregs were unable to downregulate inflammatory T cell responses. Tregs stimulated with IL-27 expressed substantially enhanced suppressive function both in vitro and in vivo. IL-27 stimulation of Tregs induced expression of LAG3, a surface molecule implicated in negatively regulating immune responses. LAG3 expression in IL-27-stimulated Tregs was critical to mediate suppressive Treg function. Finally, human Tregs also displayed enhanced suppressive function and LAG3 expression in response to IL-27 stimulation. Taken together, our results highlight a novel function of the IL-27/LAG3 axis in Treg regulation of inflammatory responses in the intestine. FACS purified Foxp3+ Tregs were stimulated in the presence of media or IL-27 to compare IL-27 induced gene profiles. Four samples (media stimulated or IL-27-stimulated) were collected from four independent experiments. Genes altered by IL-27 treatment were compared to those of media stimulated Tregs.
2015-11-01 | E-GEOD-63455 | biostudies-arrayexpress
Project description:Regulatory T cells (Tregs) are gatekeepers of immune homeostasis and characterized by expression of Foxp3, which maintains Treg identity. The transcriptional activator CREB critically stabilizes Foxp3 expression in vitro. Here we demonstrate that in mice with a Foxp3-specific knockout of CREB, Tregs show a reduced Foxp3 expression in vivo, but surprisingly enhanced expression of IL-13, IL-10, ST-2 and CREM. This rendered such Tregs highly suppressive in vitro and prevents disease activity in Th1 models like T cell mediated transfer colitis in an IL-10 dependent way. On the other hand, type 2 B cell responses were enhanced resulting in high IgE levels and susceptibility towards experimental asthma. Our data suggest that CREB expression in Tregs is important for the balance between Th1 and Th2 responses by regulating ST-2 and IL-10.
2022-12-01 | GSE157693 | GEO
Project description:Colorectal cancers are the third most common type of cancer in the world. Peritoneal carcinomatosis and intraabdominal acid development occur in advanced stages of colorectal cancers.
It is known that the immune system plays an important role in tumor development or tumor eradication. Differentiation of T cells towards Th2 and regulatory T cells is also reported to be effective in tumor progression.
Among the mechanisms of escape from the immune system, changes in the tumor microenvironment play an important role. The role of regulatory T lymphocytes, a subgroup of T cells that play a regulatory role by suppressing the function of other T lymphocytes, is to reduce the chronic immune response against viruses, tumors and patients’s own antigens. The common feature of all Tregs is that they secrete one or more anti-inflammatory molecules such as IL-10, TGFβ or IL-35. High levels of Tregs have been found in peripheral blood, tumor tissue and lymph nodes in patients with malignancy.
In our study, it is aimed to evaluate whether there is a difference in intraabdominal ascites fluid T helper cytokine levels in patients with end-stage colorectal cancers compared to patients without malignancy.
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Project description:The immune-suppressive features often possessed by invasive tumors hamper effective anti-tumor immunity. In this context, tumor-infiltrating regulatory T cells (Tregs) have been widely implied, principally as unwanted suppressors of anti-tumor immune responses. However, while many studies have focused on tumor-infiltrating Tregs, the function and signaling of Tregs in tumor-associated lymph nodes is largely unknown. In this study, we set out to clarify how immune signaling in lymph nodes is impacted by its contact to the tumour. Because muscle-invasive urothelial bladder cancer (MIBC) represent an immunogenic cancer were Tregs are accumulated and sentinel nodes (SNs) can be efficiently detected, we explored the protein expression of T-cells in SNs and non-SNs of MIBC patients. Proteomic analysis of Tregs and effector T-cells in SN and non-draining lymph nodes found SN-Tregs in MIBC patients to up-regulate growth and immune signaling pathways, the cytokine IL-16 being central in the signaling network. Experimental validation showed that in Tregs, tumoral factors increase IL-16 processing into bioactive forms and increase FOXP3 expression. In conclusion, altered IL-16 processing caused by tumour-released factors stimulate expansion of SN-Tregs in MIBC, creating an immunosuppressive environment and contributing to immune escape.
2020-09-09 | PXD009569 | Pride
Project description:Since the role of cord blood (CB) regulatory T cells (Tregs) for the suppression of the allogeneic T-cell response is under investigation, we analyzed and compared the functional properties and gene expression profile of Tregs expanded from CB units or from the peripheral blood (PB) of helathy donors. Tregs were purified from 23 CB units and from the PB of 13 donors and expanded for 6 days with anti-CD3, anti-CD28 and IL-2. Immunophenotypic analyses were performed, and suppressor activity of expanded Tregs was measured in mixed lymphocyte reaction (MLR) cultures. The IL-10 production capacity was tested and gene expression profile experiments were performed on 6 Tregs from PB and 4 from CB. CB and PB Tregs had similar immunophenotypic features. Tregs from CB presented a higher expansion capacity and genomic characterization showed in CB-derived Tregs a significant enrichments of genes involved in cell proliferation, chromatin modification and regulation of gene expression in CB-derived Tregs. All samples were positive for the Foxp3 gene and protein after expansion. CB and PB expanded Tregs exerted a comparable and potent suppressive function of MLR and presented a high in vitro IL-10 production capacity. Gene profile analysis also revealed for PB Tregs a significant enrichments of genes involved in the adaptive immune response. Comparison of the transcriptional profile of T-REGS derived either from cord blood or peripheral blood. 6 highly purified T-regs samples derived from peripheral blood of healthy donors were compared to highly purified T-regs from cord blood.
2010-12-31 | E-GEOD-22501 | biostudies-arrayexpress
Project description:Foxp3 expressing regulatory T cells (Tregs) are the central regulator of immune homeostasis and tolerance. As it is believed that proper Treg function is compromised under inflammatory conditions, exploring a pathway that enhances Treg function is of great importance. In this study, we report that IL-27, an IL-12 family cytokine known to play both pro- and anti-inflammatory role in T cells, plays a pivotal role in Treg function to control T cell-induced colitis. Unlike WT Tregs capable of inhibiting colitogenic T cell expansion and inflammatory cytokine expression, IL-27R-deficient Tregs were unable to downregulate inflammatory T cell responses. Tregs stimulated with IL-27 expressed substantially enhanced suppressive function both in vitro and in vivo. IL-27 stimulation of Tregs induced expression of LAG3, a surface molecule implicated in negatively regulating immune responses. LAG3 expression in IL-27-stimulated Tregs was critical to mediate suppressive Treg function. Finally, human Tregs also displayed enhanced suppressive function and LAG3 expression in response to IL-27 stimulation. Taken together, our results highlight a novel function of the IL-27/LAG3 axis in Treg regulation of inflammatory responses in the intestine.
2015-11-01 | GSE63455 | GEO
Project description:The mechanistic target of rapamycin (mTOR) pathway integrates diverse environmental inputs, including immune signals and metabolic cues, to direct T cell fate decisions1. Activation of mTOR, comprised of mTORC1 and mTORC2 complexes, delivers an obligatory signal for proper activation and differentiation of effector CD4+ T cells2,3, whereas in the regulatory T cell (Treg) compartment, the Akt-mTOR axis is widely acknowledged as a crucial negative regulator of Treg de novo differentiation4-8 and population expansion9. However, whether mTOR signaling affects the homeostasis and function of Tregs remains largely unexplored. Here we show that mTORC1 signaling is a pivotal positive determinant of Treg function. Tregs have elevated steady-state mTORC1 activity compared to naïve T cells. Signals via T cell receptor (TCR) and IL-2 provide major inputs for mTORC1 activation, which in turn programs suppressive function of Tregs. Disruption of mTORC1 through Treg-specific deletion of the essential component Raptor leads to a profound loss of Treg suppressive activity in vivo and development of a fatal early-onset inflammatory disorder. Mechanistically, Raptor/mTORC1 signaling in Tregs promotes cholesterol/lipid metabolism, with the mevalonate pathway particularly important for coordinating Treg proliferation and upregulation of suppressive molecules CTLA-4 and ICOS to establish Treg functional competency. In contrast, mTORC1 does not directly impact the expression of Foxp3 or anti- and pro-inflammatory cytokines in Tregs, suggesting a non-conventional mechanism for Treg functional regulation. Lastly, we provide evidence that mTORC1 maintains Treg function partly through inhibiting the mTORC2 pathway. Our results demonstrate that mTORC1 acts as a fundamental ‘rheostat’ in Tregs to link immunological signals from TCR and IL-2 to lipogenic pathways and functional fitness, and highlight a central role of metabolic programming of Treg suppressive activity in immune homeostasis and tolerance. We used microarrays to explore the gene expression profiles differentially expressed in regulatory T-cells from wild-type and CD4(cre) x Raptor(fl/fl) mice
2013-06-24 | E-GEOD-46693 | biostudies-arrayexpress
Project description:Since the role of cord blood (CB) regulatory T cells (Tregs) for the suppression of the allogeneic T-cell response is under investigation, we analyzed and compared the functional properties and gene expression profile of Tregs expanded from CB units or from the peripheral blood (PB) of helathy donors. Tregs were purified from 23 CB units and from the PB of 13 donors and expanded for 6 days with anti-CD3, anti-CD28 and IL-2. Immunophenotypic analyses were performed, and suppressor activity of expanded Tregs was measured in mixed lymphocyte reaction (MLR) cultures. The IL-10 production capacity was tested and gene expression profile experiments were performed on 6 Tregs from PB and 4 from CB. CB and PB Tregs had similar immunophenotypic features. Tregs from CB presented a higher expansion capacity and genomic characterization showed in CB-derived Tregs a significant enrichments of genes involved in cell proliferation, chromatin modification and regulation of gene expression in CB-derived Tregs. All samples were positive for the Foxp3 gene and protein after expansion. CB and PB expanded Tregs exerted a comparable and potent suppressive function of MLR and presented a high in vitro IL-10 production capacity. Gene profile analysis also revealed for PB Tregs a significant enrichments of genes involved in the adaptive immune response.
2010-12-31 | GSE22501 | GEO
Project description:Thymic-derived natural T regulatory cells (nTregs) are characterized by functional and phenotypic heterogeneity. Recently, a small fraction of peripheral Tregs have been shown to express Klrg1, but it remains unclear the extent Klrg1 defines a unique Treg subset. Here we show that Klrg1+ Tregs represent a terminally differentiated Treg subset derived from Klrg1- Tregs. This subset is a recent antigen-responsive and a highly activated short-lived Treg population that expresses enhanced levels of Treg suppressive molecules and that preferentially resides within mucosal tissues. The development of Klrg1+ Tregs also requires extensive IL-2R signaling. This activity represents a distinct function for IL-2, independent from its contribution to Treg homeostasis and competitive fitness. These and other properties are analogous to terminally differentiated short-lived CD8+ T effector cells. Our findings suggest that an important pathway driving antigen-activated conventional T lymphocytes also operates for Tregs. Gene expression analysis was performed of this and other Treg subsets based on expression of CD62L, CD69, and Klrg1 to define the molecular properties of Klrg1+ Tregs and its relationship to other Treg subsets found in the peripheral immune tissues. Mice were euthanized, spleen cell preparations were made, and each Treg subset was isolated by FACS cell sorting. RNA was immediately prepared for processing.
2012-08-06 | E-GEOD-36527 | biostudies-arrayexpress