Copper control of the suppressive capacity in regulatory T cells [RNA-Seq]
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE304478 | GEO | 2026/04/03
REPOSITORIES: GEO
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Project description:Fine-tuning nutrient flow and energy production is required to sustain the functionality and survival of Tregs, yet key factors and pathways remain to be identified. Here, we show that, mitochondrial activity is a superior property over activation markers for Treg functionality. Through a screen of mitochondrial inhibitory compounds, we reveal that copper chelators/ionophores modulate mitochondrial activity. Tregs activated in vitro and from individuals with psoriasis and rheumatoid arthritis obscure a greater labile copper pool compared to controls. We characterize Slc31a1 as a major copper transporter in Treg, which supports oxidative phosphorylation, energy production and histone acetylation at the gene loci of suppressive genes to maintain the transcription of suppressive molecules and Treg functionality. This process is vital for peripheral immune tolerance. Our findings underscore the role of copper metabolism in Treg biology, which may offer therapeutic strategy for treating autoimmune diseases.
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Project description:Fine-tuning nutrient flow and energy production is required to sustain the functionality and survival of Tregs, yet key factors and pathways remain to be identified. Here, we show that, mitochondrial activity is a superior property over activation markers for Treg functionality. Through a screen of mitochondrial inhibitory compounds, we reveal that copper chelators/ionophores modulate mitochondrial activity. Tregs activated in vitro and from individuals with psoriasis and rheumatoid arthritis obscure a greater labile copper pool compared to controls. We characterize Slc31a1 as a major copper transporter in Treg, which supports oxidative phosphorylation, energy production and histone acetylation at the gene loci of suppressive genes to maintain the transcription of suppressive molecules and Treg functionality. This process is vital for peripheral immune tolerance. Our findings underscore the role of copper metabolism in Treg biology, which may offer therapeutic strategy for treating autoimmune diseases.
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Project description:Copper homeostasis has been linked to human health and hematopoiesis. However, the underlying mechanisms remain elusive. Here, we demonstrate the pivotal role of the transporter Slc31a1(Ctr1) in copper uptake, during postnatal hematopoiesis. Specifically, Slc31a1-mediated copper transport sustains the differentiation and commitment of multipotent progenitors from short-term hematopoietic stem cells (HSCs). By transcriptome analyses we reveal a disrupted differentiation program in the hematopoietic stem and progenitor cells (HSPCs) derived from diet-induced copper deficiency mice or hematopoietic-specific Slc31a1 knockout (vKO) mice. Further, we show that Slc31a1 and copper are indispensable for sustaining mitochondrial activity via Complex IV within HSPCs. Notably, the copper ionophore elesclomol significantly ameliorates severe anemia in vKO mice and partially recovers mitochondrial function in vKO HSPCs. These findings demonstrate the critical role of Slc31a1/copper in maintaining HSC homeostasis via modulation of mitochondrial energy metabolism; thus, shedding light on the molecular basis of HSC fate decisions while opening new avenues to maintaining functional HSCs.
2025-12-31 | GSE275760 | GEO
Project description:Copper homeostasis has been linked to human health and hematopoiesis. However, the underlying mechanisms remain elusive. Here, we demonstrate the pivotal role of the transporter Slc31a1(Ctr1) in copper uptake, during postnatal hematopoiesis. Specifically, Slc31a1-mediated copper transport sustains the differentiation and commitment of multipotent progenitors from short-term hematopoietic stem cells (HSCs). By transcriptome analyses we reveal a disrupted differentiation program in the hematopoietic stem and progenitor cells (HSPCs) derived from diet-induced copper deficiency mice or hematopoietic-specific Slc31a1 knockout (vKO) mice. Further, we show that Slc31a1 and copper are indispensable for sustaining mitochondrial activity via Complex IV within HSPCs. Notably, the copper ionophore elesclomol significantly ameliorates severe anemia in vKO mice and partially recovers mitochondrial function in vKO HSPCs. These findings demonstrate the critical role of Slc31a1/copper in maintaining HSC homeostasis via modulation of mitochondrial energy metabolism; thus, shedding light on the molecular basis of HSC fate decisions while opening new avenues to maintaining functional HSCs.
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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).
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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: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
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