Stat3 Programs Th17-Specific Regulatory T Cells to Control GN

Kluger, Malte A.; Luig, Michael; Wegscheid, Claudia; Goerke, Boeren; Paust, Hans‐Joachim; Brix, Silke R.; Yan, Isabell; Mittrücker, Hans‐Willi; Hagl, Beate; Renner, Ellen D.; Tiegs, Gisa; Wiech, Thorsten; Stahl, Rolf A.K.; Panzer, Ulf; Steinmetz, Oliver M.

doi:10.1681/asn.2013080904

Cited by 70 publications

(104 citation statements)

References 48 publications

(61 reference statements)

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“…These Treg17 cells depend on activation of the transcription factor Stat3. 4,34 Because Stat3 is a known inducer of RORgt, we aimed to investigate whether biTregs might belong to this newly identified Treg subset. However, biTregs were present at normal percentages in mice lacking Stat3 activation in Tregs, indicating that they are a population different from Treg17.…”

Section: Discussionmentioning

confidence: 99%

“…4 For intracellular and intranuclear staining, samples were processed using a commercial intranuclear staining kit (Foxp3-Kit; Ebioscience). Fluorochrome-labeled antibodies against IL-17, IFNg, Foxp3, Ki67, T-Bet (all Ebioscience), RORgt (BD Biosciences, Heidelberg, Germany), and Helios (Biolegend) were employed as recently published.…”

Section: Flow Cytometrymentioning

confidence: 99%

“…1 Importantly, it was suggested that lineage-specific Tregs might exist which correspond to their proinflammatory Th counterpart. [2][3][4] Treg1 cells preferentially downregulate Th1 responses, while Treg17 cells dampen Th17 responses. Interestingly, programming of these lineage-specific Tregs seems to rely on some of the same transcription factors needed for induction of the opposing Th cell population.…”

mentioning

confidence: 99%

“…Recently, using the nephrotoxic nephritis (NTN) model of crescentic GN, we could show that activation of the transcription factor Stat3 is not only crucial for generation of nephritogenic Th17 cells but also programs their protective Treg17 cell counterpart. 4 This prompted the question whether other Th17-related transcription factors are active in regulatory T cells as well. Interestingly, pioneering work by the group of Eberl could show that not only Stat3 but also the second Th17 master transcription factor RORgt is expressed by a subpopulation of Foxp3 + Tregs (hereafter referred to as biTregs).…”

mentioning

confidence: 99%

“…22 In line, both RORgt and its target cytokine IL-17 were found to be central proinflammatory mediators of GN. 4,20,23,24 It is thus tempting to speculate that cells expressing not only one but both of these potent transcription factors, RORgt and Foxp3, play a significant role in inflammatory renal disease. Importantly, given the dominant role of RORgt in development of pathogenic Th17 responses, multiple research groups and companies are in the process of establishing blocking agents.…”

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confidence: 99%

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RORγt+Foxp3+ Cells are an Independent Bifunctional Regulatory T Cell Lineage and Mediate Crescentic GN

Kluger

Meyer

Nosko

et al. 2016

Journal of the American Society of Nephrology

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Cells expressing both the regulatory T cell (Treg)-inducing transcription factor Foxp3 and the Th17 transcription factor RORgt have been identified (biTregs). It is unclear whether RORgt + Foxp3 + biTregs belong to the Th17-specific Treg17 cells, represent intermediates during Treg/Th17 transdifferentiation, or constitute a distinct cell lineage. Because the role of biTregs in inflammatory renal disease is also unknown, we studied these cells in the nephrotoxic nephritis (NTN) model of acute crescentic GN. Induction of NTN resulted in rapid renal and systemic expansion of biTregs. Notably, analyses of the biTreg expression profile revealed production of both anti-inflammatory (IL-10, IL-35) and proinflammatory (IL-17) cytokines. Additionally, biTregs expressed a signature of surface molecules and transcription factors distinct from those of Th17 cells and conventional Tregs (cTregs), and biTregs were identified in Treg17-deficient mice. Finally, fate reporter and cell transfer studies confirmed that biTregs are not Treg/Th17 transdifferentiating cells. Therapeutic transfer of biTregs suppressed the development of nephritis to an extent similar to that observed with transferred cTregs, but in vitro studies indicated different mechanisms of immunosuppression for biTregs and cTregs. Intriguingely, as predicted from their cytokine profile, endogenous biTregs displayed additional proinflammatory functions in NTN that were abrogated by cellspecific deletion of RORgt. In summary, we provide evidence that RORgt + Foxp3 + biTregs are a novel and independent bifunctional regulatory T cell lineage distinct from cTregs, Treg17 cells, and Th17 cells. Furthermore, biTregs appear to contribute to crescentic GN and hence may be novel therapeutic targets.

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Section: Discussionmentioning

confidence: 99%

Section: Flow Cytometrymentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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RORγt+Foxp3+ Cells are an Independent Bifunctional Regulatory T Cell Lineage and Mediate Crescentic GN

Kluger

Meyer

Nosko

et al. 2016

Journal of the American Society of Nephrology

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Investigation on the regulatory T cells signature and relevant Foxp3/STAT3 axis in esophageal cancer

Yang

Zhao

Wang³

et al. 2022

Cancer Medicine

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Background: Regulatory T cells (Tregs) have an important role in accelerating the immunosuppression of tumor. Tregs regulation is a hopeful strategy to improve the dismal prognosis of Esophageal cancer (EC), while its mechanisms have not yet been fully clarified. Methods: To characterize the role of Tregs in EC, we comprehensively explored its prognostic value, clinical pathology partnership, related biological functions and potential mechanisms at transcriptome level. Through the integrated analysis of GEO and TCGA datasets, we comprehensively evaluated the Tregs infiltration patterns in EC patients. The correlation between Tregs infiltration and genomic characteristics, as well as biological functions were analyzed by a variety of computational algorithms. Results:We observed that Tregs were significantly upregulated in EC and involved in various immune processes. According to TCGA and GEO transcriptional classification schemes, Tregs specific genes were observed to be highly expressed in tumor samples, as well as were closely associated with poor prognosis and worse clinical outcomes. In addition, EC patients can be stratified into high-risk and low-risk immune subgroups according to Tregs/macrophages infiltration level, and the results showed significant differences in tumor development, biological processes and probe gene expression pattern. The multi-variate analysis revealed that the interaction between STAT3 and Foxp3 was a potential prognostic signature of Tregs in EC, especially the modulation effect of STAT3 on Foxp3 expression, which has not been well studied in EC. We also identified that STAT3 and Foxp3 expression presented a high accuracy in predicting Tregs infiltration level in EC patients (AUC: 0.817; 95% CI: 0.756-0.878). Conclusions: Our results revealed that Tregs have the potential to predict prognosis and tumor deterioration in EC patients. A comprehensive landscape of Tregs regulation mechanisms will help us interpret the immunosuppression of tumor microenvironment (TME) and novel strategies for EC immunotherapy.

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The IL–10/STAT3 axis: Contributions to immune tolerance by thymus and peripherally derived regulatory T‐cells

Schmetterer

Pickl

2017

Eur J Immunol

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The signal transducer and activator of transcription (STAT) proteins are important mediators for the integration of extrinsic signals provided by cytokines and hormones and thereby adapt cellular processes to their surroundings. In the past decade, the involvement of STAT3 in the regulation of T-cell responses has become a topic of increasing interest. STAT3 is activated in response to multiple cytokines, many of which have been shown to influence T-cell responses. Interestingly, many of these factors have been described with apparent opposing roles, such as the highly pro-inflammatory potency of IL-6 and the anti-inflammatory properties of IL-10, thus raising the possibility that STAT3 signaling may fulfill diverse roles in CD4 + T-cells. Here, we review the contribution of STAT3 to the induction and function of both peripherally induced as well as thymus-derived regulatory T-cells. Indeed, experimental approaches as well as studies of human patients suffering from e.g. Job's (hyper IgE) syndrome or inflammatory bowel disease (IBD) have now established a clear-cut role for the IL-10/STAT3 axis in immune tolerance; further understanding of these processes could lead to novel therapeutic approaches for autoimmune diseases.Keywords: IL-10 r Regulatory T-cells r STAT3 r Tolerance r Tr1 cells IntroductionThe immune system evolved to discriminate between self and nonself determinants, maintaining homeostasis by recognizing and eliminating pathogenic microorganisms while sparing all the constituents of our own body [1]. It is an explicitly delicate task, on the one hand, to precisely recognize foreign invaders but, on the other hand, to strictly prevent autoimmunity to self-antigens. Apart from mechanisms deleting or anergizing lymphocytes expressing self-reactive antigen receptors centrally, i.e. at the level of thymic development for T-cells or during B-cell maturation Correspondence: Winfried F. Pickl e-mail: winfried.pickl@meduniwien.ac.at in the bone marrow and thus establishing central tolerance, several types of regulatory T-cells are also being generated in our body, both centrally and peripherally, contributing to the maintenance of immune tolerance [2,3]. In the past, transcription factors (TFs) driving specific T helper programs while inhibiting others have been described. Among them are TFs responsible for inducing Treg phenotype and function, such as the forkhead box protein 3, Foxp3, which nowadays is regarded as the master TF of thymus-derived Treg (tTreg) development during thymic T-cell maturation [4][5][6]. Moreover, recent discoveries in the authors' laboratory and others suggest that the TF signal transducer and activator of transcription 3, STAT3, seems to be critically involved in generating a hypo-responsive T-cell subtype [7], which shares, besides their hypo-responsiveness, several additional attributes with human T regulatory type 1 (Tr1) cells, such as elevated About IL-10 and STAT3Although initially described in T-cells, IL-10 is also produced by a large number of other immune cell types, ...

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Stat3 Programs Th17-Specific Regulatory T Cells to Control GN

Cited by 70 publications

References 48 publications

RORγt+Foxp3+ Cells are an Independent Bifunctional Regulatory T Cell Lineage and Mediate Crescentic GN

RORγt+Foxp3+ Cells are an Independent Bifunctional Regulatory T Cell Lineage and Mediate Crescentic GN

Investigation on the regulatory T cells signature and relevant Foxp3/STAT3 axis in esophageal cancer

The IL–10/STAT3 axis: Contributions to immune tolerance by thymus and peripherally derived regulatory T‐cells

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