Glutathione Restricts Serine Metabolism to Preserve Regulatory T Cell Function

Kurniawan, Henry; Franchina, Davide G.; Guerra, Luana; Bonetti, Lynn; Soriano-Baguet, Leticia; Grusdat, Melanie; Schlicker, Lisa; Hunewald, Oliver; Dostert, Catherine; Merz, Myriam P.; Binsfeld, Carole; Duncan, Gordon S.; Farinelle, Sophie; Nonnenmacher, Yannic; Haight, Jillian; Gupta, Dennis Das; Ewen, Anouk; Taskesen, Rabia; Halder, Rashi; Chen, Ying; Jäger, Christian; Ollert, Markus; Wilmes, Paul; Vasiliou, Vasilis; Harris, Isaac S.; Knobbe-Thomsen, Christiane B.; Turner, Jonathan D.; Mak, Tak W.; Lohoff, Michael; Meiser, Johannes; Hiller, Karsten; Brenner, Dirk

doi:10.1016/j.cmet.2020.03.004

Cited by 117 publications

(97 citation statements)

References 82 publications

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“…Accordingly, dietary intervention in the form of feeding the mutant mice on serine/glycine‐deficient chow prevents the onset of autoimmunity. In line with this finding, dampening of serine metabolism reinstated the suppressive function of Tregs, firmly linking serine metabolism to Treg function [61].…”

Section: Overview Of Metabolic Control In Treg Cellsmentioning

confidence: 75%

“…Lastly, it was shown that increased Glut1 expression in murine Tregs enhances glycolysis and proliferation driven by mTORC1. The increased mTORC1 activity impairs tTreg and pTreg suppressive capacity and decreases FoxP3 expression both in vitro and in vivo [22,61].…”

Section: Overview Of Metabolic Control In Treg Cellsmentioning

confidence: 99%

“…Collectively, current studies of energy metabolism in Tregs indicate that Treg proliferation and suppressive activity can be influenced by a variety of metabolic pathways, including anabolic signals driven by the mTORC1 axis and those arising from FoxP3‐dependent oxidative metabolism [22,61].…”

Section: Overview Of Metabolic Control In Treg Cellsmentioning

confidence: 99%

“…GSH synthesis also depends on the catalytic subunit of glutamate cysteine ligase ( Gclc ). Conditional deletion of Gclc in murine Tregs impairs their production of GSH [61]. These mutant Tregs consequently display increased levels of ROS but no apparent defects in both tTreg and pTreg homeostasis, stability or differentiation.…”

Section: Overview Of Metabolic Control In Treg Cellsmentioning

confidence: 99%

“…These mutant Tregs consequently display increased levels of ROS but no apparent defects in both tTreg and pTreg homeostasis, stability or differentiation. However, Gclc ‐deficient Tregs do show increased proliferation, activation, glycolysis, and OXPHOS, and the mutant mice develop spontaneous autoimmunity [61]. Importantly, Gclc ‐deficient Tregs show elevations in both their synthesis and uptake of serine.…”

Section: Overview Of Metabolic Control In Treg Cellsmentioning

confidence: 99%

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Regulatory T cell metabolism at the intersection between autoimmune diseases and cancer

2020

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Regulatory T cells (Tregs) are critical for peripheral immune tolerance and homeostasis, and altered Treg behavior is involved in many pathologies, including autoimmunity and cancer. The expression of the transcription factor FoxP3 in Tregs is fundamental to maintaining their stability and immunosuppressive function. Recent studies have highlighted the crucial role that metabolic reprogramming plays in controlling Treg plasticity, stability, and function. In this review, we summarize how the availability and use of various nutrients and metabolites influence Treg metabolic pathways and activity. We also discuss how Treg‐intrinsic metabolic programs define and shape their differentiation, FoxP3 expression, and suppressive capacity. Lastly, we explore how manipulating the regulation of Treg metabolism might be exploited in different disease settings to achieve novel immunotherapies.

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Section: Overview Of Metabolic Control In Treg Cellsmentioning

confidence: 75%

Section: Overview Of Metabolic Control In Treg Cellsmentioning

confidence: 99%

Section: Overview Of Metabolic Control In Treg Cellsmentioning

confidence: 99%

Section: Overview Of Metabolic Control In Treg Cellsmentioning

confidence: 99%

Section: Overview Of Metabolic Control In Treg Cellsmentioning

confidence: 99%

See 3 more Smart Citations

Regulatory T cell metabolism at the intersection between autoimmune diseases and cancer

2020

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Oxidative stress in the tumor microenvironment in gastric cancer and its potential role in immunotherapy

Zhang

et al. 2023

FEBS Open Bio

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Gastric cancer (GC) is the fourth leading cause of cancer‐related death and the fifth most common malignant tumor globally. However, the clinical efficacy of conventional therapies is limited. Currently, immunotherapy is considered an effective therapeutic strategy for the management of various cancers, especially GC, but is of only limited benefit for GC patients. Accumulating evidence has revealed that oxidative stress plays a critical role in the regulation of immune responses within the tumor microenvironment (TME), affecting the efficacy of immunotherapies. Reactive oxygen species exert critical roles in enhancing antigen presentation, regulating immune responses, and preventing immunoescape. In this review, we summarize the dominant cancer immunotherapeutic strategies and describe the interaction between oxidative stress and the immune TME. We emphasize the underlying mechanisms of the efficacy of cancer immunotherapy, which involves its effects on oxidative stress, in the context of GC. We also highlight the therapeutic potential of regulating oxidative stress to improve immunotherapies, which may have benefits for clinical practice.

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Glutathione Pulse Therapy: Promote Spatiotemporal Delivery of Reduction‐Sensitive Nanoparticles at the “Cellular Level” and Synergize PD‐1 Blockade Therapy

et al. 2022

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Spatiotemporal delivery of nanoparticles (NPs) at the "cellular level" is critical for nanomedicine, which is expected to deliver as much cytotoxic drug into cancer cells as possible when NPs accumulate in tumors. However, macrophages and cancer-associated fibroblasts (CAFs) that are present within tumors limit the efficiency of spatiotemporal delivery. To overcome this limitation, glutathion pulse therapy is designed to promote reduction-sensitive Larotaxel (LTX) prodrug NPs to escape the phagocytosis of macrophages and penetrate through the stromal barrier established by CAFs in the murine triple negative breast cancer model. This therapy improves the penetration of NPs in tumor tissues as well as the accumulation of LTX in cancer cells, and remodels the immunosuppressive microenvironment to synergize PD-1 blockade therapy. More importantly, a method is established that can directly observe the biodistribution of NPs between different cells in vivo to accurately quantify the target drugs accumulated in these cells, thereby advancing the spatiotemporal delivery research of NPs at the "cellular level."

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Glutathione Restricts Serine Metabolism to Preserve Regulatory T Cell Function

Cited by 117 publications

References 82 publications

Regulatory T cell metabolism at the intersection between autoimmune diseases and cancer

Regulatory T cell metabolism at the intersection between autoimmune diseases and cancer

Oxidative stress in the tumor microenvironment in gastric cancer and its potential role in immunotherapy

Glutathione Pulse Therapy: Promote Spatiotemporal Delivery of Reduction‐Sensitive Nanoparticles at the “Cellular Level” and Synergize PD‐1 Blockade Therapy

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