The thioredoxin‐1 and glutathione/glutaredoxin‐1 systems redundantly fuel murine B‐cell development and responses

Muri, Jonathan; Thut, Helen; Heer, Sebastian; Krueger, Caroline C.; Bornkamm, Georg W.; Bachmann, Martin F.; Köpf, Manfred

doi:10.1002/eji.201848044

Cited by 29 publications

(24 citation statements)

References 73 publications

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“…The Trx1 system promotes nucleotide biosynthesis during metabolic reprogramming and rapid expansion of lymphocytes [6,8]. In this study, we report that the negative regulator of Trx1, namely Txnip, restrains T‐ and B‐cell proliferation during immune responses but is dispensable for their homeostatic maintenance.…”

Section: Discussionmentioning

confidence: 84%

“…S2B–G). Overall, these results suggest that while Trx1 is crucial to sustain proliferation of immune cells [6,8,9], genetic deletion of its inhibitor Txnip does not result in uncontrolled proliferation during their development and homeostasis.…”

Section: Resultsmentioning

confidence: 99%

“…Genetic deletion of Txnrd1 in immune cells prevents T‐cell proliferation during thymic development and upon antigen exposure in the periphery due to the critical role of Trx1 in donating electrons for the synthesis of deoxynucleotides (dNTPs) by ribonucleotide reductase [8]. By contrast, follicular B2 cells have the capacity to expand in the absence of the Trx1 system by engaging the glutathione/glutaredoxin pathway for dNTP production, although the latter is less efficient in sustaining proliferation [6]. Moreover, in dendritic cells (DCs) and macrophages Trx1 induces inflammatory responses by promoting NF‐κB‐mediated transcriptional activity as well as NLRP3 inflammasome activation [9].…”

Section: Introductionmentioning

confidence: 99%

“…NADPH generated by the alternative oxidation of glucose in the pentose phosphate pathway provides the reducing power for the two main antioxidant systems in the cell, namely the thioredoxin (Trx) and the glutathione/glutaredoxin pathways [1,2]. In mammals, both systems have critical roles in the regulation of numerous cellular processes, including gene transcription, proliferation, scavenging of ROS, and apoptosis [1,3,4], and are known to partially Correspondence: Prof. Manfred Kopf e-mail: Manfred.Kopf@ethz.ch compensate for each other when the function of one system is compromised [5,6].…”

Section: Introductionmentioning

confidence: 99%

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The thioredoxin‐1 inhibitor Txnip restrains effector T‐cell and germinal center B‐cell expansion

2020

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Thioredoxin‐1 (Trx1) is a vital component for cellular redox homeostasis. In T cells, Trx1 donates electrons for the de novo synthesis of deoxyribonucleotides to allow rapid cell proliferation. The Trx‐interacting protein (Txnip) binds to the reduced Trx1 and inhibits its activity. However, the role of Txnip in adaptive immunity in vivo is unknown. Here, we show that absence of Txnip increased proliferation of effector T cells and GC B‐cell responses in response to lymphocytic choriomeningitis virus and Qβ virus‐like particles, respectively, but did not affect development and homeostasis of T and B cells. While downregulation of Txnip and concomitant upregulation of Trx1 is critical for rapid T‐cell expansion upon viral infection, re‐expression of Txnip and consequently inhibition of Trx1 is important to restrain late T‐cell expansion. Importantly, we demonstrated that T‐cell receptor (TCR) engagement but not CD28 costimulation is critically required for Txnip downregulation. Thus, this study further uncovers positive and negative control of lymphocyte proliferation by the Trx1 system.

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Section: Discussionmentioning

confidence: 84%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The thioredoxin‐1 inhibitor Txnip restrains effector T‐cell and germinal center B‐cell expansion

2020

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“…Reduced thioredoxins are potent reductases with a relatively broad spectrum of substrates that partially overlaps with the glutathione system. The thioredoxin and glutathione systems have been shown to play crucial but partially redundant roles in B cells . NADPH produced by the PPP acts as an electron donor for both the thioredoxin and glutathione pathway.…”

Section: Consequences Of Disrupted Metabolic Homeostasismentioning

confidence: 99%

The role of metabolic checkpoint regulators in B cell survival and transformation

Jellusova

2020

Immunological Reviews

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In response to mitogenic stimulation, B cells activate different pro-anabolic signaling pathways such as c-Myc-and mTORC1-dependent networks to satisfy the energetic demands of biomass synthesis and proliferation. In order to preserve viability and function, cell growth cannot progress unchecked and must be adjusted according to the availability of nutrients. Nutrient-sensing proteins such as AMPK antagonize mTORC1 activity in response to starvation. If pro-anabolic signaling pathways are aberrantly activated, B cells may lack the metabolic capacity to accommodate their energetic needs, which can lead to cell death. On the other hand, metabolic hyperactivation is a salient feature of cancer cells, suggesting that mechanisms exist, which allow B cells to cope with metabolic stress. The aim of this review is to discuss how B cells respond to a mismatch between energy supply and demand and what the consequences are of metabolic dysregulation in normal and malignant B cells. K E Y W O R D Sanabolism, autophagy, B cells, metabolic stress, mTORC1, senescence

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The thioredoxin system: Balancing redox responses in immune cells and tumors

Muri

Köpf

2022

Eur J Immunol

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The thioredoxin (TRX) system is an important contributor to cellular redox balance and regulates cell growth, apoptosis, gene expression, and antioxidant defense in nearly all living cells. Oxidative stress, the imbalance between reactive oxygen species (ROS) and antioxidants, can lead to cell death and tissue damage, thereby contributing to aging and to the development of several diseases, including cardiovascular and allergic diseases, diabetes, and neurological disorders. Targeting its activity is also considered as a promising strategy in the treatment of cancer. Over the past years, immunologists have established an essential function of TRX for activation, proliferation, and responses in T cells, B cells, and macrophages. Upon activation, immune cells rearrange their redox system and activate the TRX pathway to promote proliferation through sustainment of nucleotide biosynthesis, and to support inflammatory responses in myeloid cells by allowing NF-κB and NLRP3 inflammasome responses. Consequently, targeting the TRX system may therapeutically be exploited to inhibit immune responses in inflammatory conditions. In this review, we summarize recent insights revealing key roles of the TRX pathway in immune cells in health and disease, and lessons learnt for cancer therapy.

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The thioredoxin‐1 and glutathione/glutaredoxin‐1 systems redundantly fuel murine B‐cell development and responses

Cited by 29 publications

References 73 publications

The thioredoxin‐1 inhibitor Txnip restrains effector T‐cell and germinal center B‐cell expansion

The thioredoxin‐1 inhibitor Txnip restrains effector T‐cell and germinal center B‐cell expansion

The role of metabolic checkpoint regulators in B cell survival and transformation

The thioredoxin system: Balancing redox responses in immune cells and tumors

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