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Tregs promote benefitial effects of exercise by reining in interferon-mediated damage to muscle mitochondria

ABSTRACT: Exercise is a salubrious activity: it enhances physical performance and reduces the risk of modern afflictions such as cardiovascular disease, type 2 diabetes, and cancer. Exercise characteristically incites an inflammatory response, notably in skeletal muscles. While some key innate and adaptive effector immunocytes have been identified, counteracting regulatory elements remain obscure. We have addressed the roles of Foxp3+CD4+ regulatory T cells (Tregs) in the healthful activities of exercise via immunologic, transcriptomic, histologic, metabolic, and biochemical analyses of acute and chronic exercise models. Exercise rapidly induced expansion of the muscle Treg compartment, thereby guarding against over-exuberant production of interferons and consequent metabolic disruptions, particularly mitochondrial aberrancies. Importantly, typical performance enhancements resulting from exercise training were dampened in the absence of Tregs. Thus, exercise is a natural Treg booster with therapeutic potential in disease and aging contexts.

ORGANISM(S): Mus musculus

PROVIDER: GSE220181 | GEO | 2023/08/01

REPOSITORIES: GEO

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Regulatory T cells promote endurance exercise adaptation by shielding muscle mitochondria from damage

Project description:<p>Exercise enhances physical performance and reduces the risk of many disorders such as cardiovascular disease, type 2 diabetes, dementia and cancer. Exercise characteristically incites an inflammatory response, notably in skeletal muscles. While some effector mechanisms have been identified, regulatory elements activated in response to exercise remain obscure. Here, we have addressed the roles of Foxp3+CD4+ regulatory T cells (Tregs) in the healthful activities of exercise via immunologic, transcriptomic, histologic, metabolic and biochemical analyses of acute and chronic murine exercise models. Exercise rapidly induced expansion of the muscle Treg compartment, thereby guarding against over-exuberant production of interferon gamma and consequent metabolic disruptions, particularly mitochondrial aberrancies. Importantly, the performance-enhancing effects of exercise training were dampened in the absence of Tregs. Thus, exercise is a natural Treg booster with therapeutic potential in disease and aging contexts.</p>

2023-10-10 | MTBLS8391 | MetaboLights

CD49f defines a subset of dysfunctional regulatory T cells circulating in the human peripheral blood

Project description:The therapeutic use of regulatory T cells (Tregs) in patients with autoimmune disorders has been hampered by the biological variability of memory Treg populations in the peripheral blood. In this study, we reveal through a combination of quantitative proteomic, multiparametric flow cytometry, RNA-seq data analysis and functional assays, that CD49f is heterogeneously expressed among human Tregs and impacts their immunomodulatory function. High expression of CD49f defines a subset of dysfunctional Tregs in the human blood characterized by a Th17-like phenotype and impaired suppressive capacity. CD49f is similarly distributed between naïve and memory Tregs and impacts the expression of CD39, CTLA-4, FoxP3 and CCR6 specifically in the memory compartment. Accumulation of CD49f high memory Tregs in the blood of ulcerative colitis patients correlates with disease severity. Our results highlight important considerations for Treg immunotherapy design in patients with inflammatory bowel disease which could possibly extend to other autoimmune disorders.

2021-08-06 | PXD022095 | Pride

Tracking adipose-tissue Treg provenance, dependencies, and activities via T cell receptor transgenic mice

Project description:Regulatory T (Treg) cells located within parenchymal tissues safeguard tissue homeostasis. A paradigmatic "tissue-Treg" population is that found in visceral-adipose tissue (VAT) of male mice. VAT-Treg cells have a unique transcriptome, are clonally expanded, and promote metabolic health through effects on local immunocytes and adipocytes. Because of their rarity and inaccessibility, cardinal questions such as what factors control their accumulation in fat and when/where/how do they adopt their distinctive phenotype remained unanswered. We addressed these issues using VAT- Treg T-cell-receptor (TCR) transgenic mice. Accumulation of VAT-Tregs was driven by combined effects of TCR specificity, Foxp3 expression, and a cell-intrinsic response to interleukin-33. Their characteristic phenotype emerged in two stages: a minority of splenic Treg cells weakly up-regulated a slice of the VAT-Treg transcriptional signature, reflecting cell activation, but the definitive phenotype, arming cells for fat survival, was manifest only in VAT. This deeper understanding of tissue-Treg generation should facilitate precision-targeting strategies.

2018-06-08 | GSE113412 | GEO

Quantitative Proteomics Reveals Specialized Wiring of Signaling Pathways that Protects Human Regulatory T Cell Identity - 6 populations ex vivo

Project description:Regulatory CD4+ T cells (Tregs) are functionally distinct from conventional CD4+ T cells (Tconvs). To understand Treg identity, we compared by proteomics and transcriptomics human naïve (n) and effector (e)Tregs, Tconvs and transitional FOXP3+ cells. Only 12% of 422 differentially expressed proteins was identified as such at the mRNA level, demonstrating the importance of direct proteome measurement. Fifty-one proteins discriminated Tregs from Tconvs. This common Treg protein signature indicates altered signaling by TCR-, TNF receptor-, NFB-, PI3 kinase/mTOR-, NFAT- and STAT pathways, and unique cell biological and metabolic features. Another protein signature uniquely identified eTregs and revealed active cell division, apoptosis sensitivity and suppression of NFB- and STAT signaling. eTreg fate appears consolidated by FOXP3 outnumbering its partner transcription factors. These features explain why eTregs cannot produce inflammatory cytokines, whereas transitional FOXP3+ cells can. Collectively, our data reveal that Treg identity is defined and protected by uniquely “wired” signaling pathways. Associated GEO dataset is available at GSE90600.

2018-05-18 | PXD007744 | Pride

Quantitative Proteomics Reveals Specialized Wiring of Signaling Pathways that Protects Human Regulatory T Cell Identity - 2 populations in vitro

2018-05-18 | PXD007745 | Pride

Quantitative Proteomics Reveals Specialized Wiring of Signaling Pathways that Protects Human Regulatory T Cell Identity - 5 populations ex vivo

2018-05-18 | PXD005477 | Pride

Transcriptional profiling of Regulatory T-cells isolated from adult skin and skin draining lymph nodes (SDLNs)

Project description:Purpose: The goals of this study were to identify preferential gene expression signatures that are unique to telogen skin resident Tregs relative to peripheral Tregs Methods: Tregs from telogen skin and SDLNs were purified by cell sorting (using the Treg GFP reporter mouse line Foxp3-DTR/GFP) to generate mRNA transcription profiles. Results: Transcriptional profiling revealed a unique Skin treg signature relative to SDLN Tregs Conclusion: Our study represents the first detailed analysis of the skin Treg transcriptome. mRNA profiles of skin and SDLN Tregs isolated from 6 week old Foxp3-DTR/GFP mice.

2017-04-28 | E-GEOD-76138 | biostudies-arrayexpress

Gene expression by Treg subsets

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

Mbd2 promotes Foxp3 demethylation and T-regulatory cell function

Project description:The proposed use of Foxp3+ T-regulatory (Treg) cells as potential cellular therapy in patients with autoimmune diseases, or post-hemopoietic stem cell or organ transplantation, requires a sound understanding of the transcriptional regulation of Foxp3 expression. Conserved CpG dinucleotides in the Treg-specific demethylated region (TSDR) upstream of Foxp3 are demethylated only in stable, thymic-derived Foxp3+ Tregs. Since methyl-binding domain (Mbd) proteins recruit histone-modifying and chromatin-remodeling complexes to methylated sites, we tested whether targeting of Mbd2 might promote demethylation of Foxp3 and thereby promote Treg numbers or function. Surprisingly, while ChIP analysis showed Mbd2 binding to the Foxp3-associated TSDR site in Tregs, Mbd2 targeting by homologous recombination or siRNA decreased Treg numbers and impaired Treg suppressive function in vitro and in vivo. Moreover, we found complete TSDR demethylation in WT Tregs but >75% methylation in Mbd2-/- Tregs, whereas re-introduction of Mbd2 into Mbd2-null Tregs restored TSDR demethylation, Foxp3 gene expression and Treg suppressive function. Lastly, Mbd2-/- Tregs had markedly binding of the DNA demethylase enzyme, Tet2, in the TSDR region. These data show that Mbd2 has a key role in promoting TSDR demethylation, Foxp3 expression and Treg suppressive function. RNA from three independent samples from magnetically separated CD4+CD25+ Treg of MBD2–/– mice, compared to wild type control (all Balb/c background).

2013-09-01 | E-GEOD-48653 | biostudies-arrayexpress

IL-27 stimulation in Foxp3+ Tregs improves suppressive function and therapeutic efficacy

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

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