Extracellular redox modulation by regulatory T cells

Yan, Zhonghua; Garg, Sanjay; Kipnis, Jonathan; Banerjee, Ruma

doi:10.1038/nchembio.212

Cited by 130 publications

(183 citation statements)

References 25 publications

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“…This study showed that DCs furnish effector T cells with cs-and ic-thiols during presentation of viral and bacterial Ags and that T cells with enhanced thiol expression consume ROS and escape oxidant-induced apoptosis. In accordance with previous studies (18,20), a slight, but significant, increase in thiol expression was observed on all T cells cocultured with DCs. However, using Ag-pulsed DCs and detection of Agspecific TCR/Vb regions or tetramer technology, we found that the DC-induced thiol expression was several-fold higher in T cells specific for the presented Ag.…”

Section: Discussionsupporting

confidence: 77%

“…However, expression of thiols reportedly promotes T cell function; for example, the presence of reduced intracellular thiols (ic-thiols) in T cells and thiols expressed in cell surface proteins (cs-thiols) improves T cell reactivity and proliferation (15)(16)(17). The purported function of thiols in T cell immunity is further bolstered by the findings that dendritic cells (DCs), which are prominent APCs, release thiols (18,19) and trigger thiol expression on adjacent cells, including NK cells and T cells (18,20).…”

mentioning

confidence: 89%

“…These soluble thiols are assumed to be generated, at least in part, by DCs and other APCs that release extracellular thiols upon interaction with T cells (18,19,23,24). Uptake of cystine by DCs via the cystine/glutamate antiporter with ensuing release of cysteine and other antioxidative thiols was suggested to contribute to a reducing milieu in the extracellular space (12,18,19). To clarify the putative role of the cystine/ glutamate antiporter for the observed induction of thiols in Agspecific T cells, we added glutamate at a concentration that efficiently reduced the cystine/glutamate exchange (19).…”

Section: Discussionmentioning

confidence: 99%

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Redox Remodeling by Dendritic Cells Protects Antigen-Specific T Cells against Oxidative Stress

Martner

Aurelius

Rydström

et al. 2011

The Journal of Immunology

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Microorganisms and microbial products induce the release of reactive oxygen species (ROS) from monocytes and other myeloid cells, which may trigger dysfunction and apoptosis of adjacent lymphocytes. Therefore, T cell-mediated immunity is likely to comprise mechanisms of T cell protection against ROS-inflicted toxicity. The present study aimed to clarify the dynamics of reduced sulfhydryl groups (thiols) in human T cells after presentation of viral and bacterial Ags by dendritic cells (DCs) or B cells. DCs, but not B cells, efficiently triggered intra- and extracellular thiol expression in T cells with corresponding Ag specificity. After interaction with DCs, the Ag-specific T cells acquired the capacity to neutralize exogenous oxygen radicals and resisted ROS-induced apoptosis. Our results imply that DCs provide Ag-specific T cells with antioxidative thiols during Ag presentation, which suggests a novel aspect of DC/T cell cross-talk of relevance to the maintenance of specific immunity in inflamed or infected tissue.

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Section: Discussionsupporting

confidence: 77%

mentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

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Redox Remodeling by Dendritic Cells Protects Antigen-Specific T Cells against Oxidative Stress

Martner

Aurelius

Rydström

et al. 2011

The Journal of Immunology

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“…Metabolic labeling and pharmacological inhibition studies have revealed that the mechanism for conversion of extracellular cystine imported by dendritic cells to cysteine involves the transmembrane GSH/cysteine cycle. The increased cystine consumption and cysteine release by dendritic cells result in an approximately Ϫ30-mV decrease in the extracellular cysteine/cystine redox potential to Ϫ110 mV (14). In contrast, when dendritic cells and naïve T cells are cultured separately, the extracellular redox potentials are approximately Ϫ80 and Ϫ50 mV, respectively, consistent with dendritic cells being differentiated and T cells being fated for apoptosis in the absence of activation.…”

Section: Redox Modulation In Extracellular Compartmentmentioning

confidence: 72%

“…Mammalian cells in culture hold the extracellular cysteine/cystine redox potential at approximately Ϫ80 mV, which shifts in the reductive or oxidative direction depending on whether the cells are ready for proliferation or death ( Fig. 1A) (14,15).…”

Section: Redox Nodesmentioning

confidence: 99%

Redox outside the Box: Linking Extracellular Redox Remodeling with Intracellular Redox Metabolism

Banerjee

2012

Journal of Biological Chemistry

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171

137

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Aerobic organisms generate reactive oxygen species as metabolic side products and must achieve a delicate balance between using them for signaling cellular functions and protecting against collateral damage. Small molecule (e.g. glutathione and cysteine)-and protein (e.g. thioredoxin)-based buffers regulate the ambient redox potentials in the various intracellular compartments, influence the status of redox-sensitive macromolecules, and protect against oxidative stress. Less well appreciated is the fact that the redox potential of the extracellular compartment is also carefully regulated and is dynamic. Changes in intracellular metabolism alter the redox poise in the extracellular compartment, and these are correlated with cellular processes such as proliferation, differentiation, and death. In this minireview, the mechanism of extracellular redox remodeling due to intracellular sulfur metabolism is discussed in the context of various cell-cell communication paradigms.Life on oxygen necessitated the evolution of antioxidant systems to protect against overoxidation and to combat reactive oxygen species (ROS) 2 generated as side products from a leaky electron transfer chain. ROS are also produced in a multitude of other oxygen-metabolizing reactions and, at low levels, serve in biological signaling pathways (1, 2). At elevated levels, ROS are correlated with a plethora of complex diseases, including cardiovascular and neurodegenerative diseases and cancers (3). In addition to their widely recognized role in countering oxidative threats, antioxidant systems are vitally important for poising the intra-and extracellular redox milieus, both of which are maintained far from equilibrium. Small molecule-and proteinbased redox buffer systems, including GSH/GSSG, cysteine/ cystine, and oxidized/reduced thioredoxin, are used for thiolbased redox homeostasis essential for controlling cellular functions, e.g. gene expression, cell cycle progression, and apoptosis (4). In proteins, methionine and cysteine are the two common amino acids that can be reversibly oxidized, and their redox status can influence protein conformation and/or stability, enzymatic activity, and interactions with other protein and/or DNA partners. Oxidation of methionine leads to methionine sulfoxide, which can be reversed enzymatically, or to methionine sulfone, an overoxidized species that cannot be rescued (5). Oxidation of cysteine can lead to formation of sulfenic, sulfinic, or sulfonic acid, the latter of which represents an irreversible modification. In addition to small molecule repair systems, antioxidant enzymes are utilized for maintaining the integrity of functionally critical redox-active amino acids and include sulfiredoxin (6), methionine sulfoxide reductase (5), and thioredoxin (7), whereas enzymes such as superoxide dismutase, glutathione peroxidase, and catalase keep ROS levels at bay.The cellular redox status governs the equilibrium between oxidized versus reduced states of cysteines and methionines. The more oxidizing environment of the...

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Immunoregulation through membrane proteins modified by reducing conditions induced by immune reactions

2013

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Selected disulfide bonds in membrane proteins are labile and are thus susceptible to changes in redox potential and/or the presence of thiol isomerase enzymes. Modification of these disulfide bonds can lead to conformational changes of the protein that in turn may alter protein activity and function. This occurs in the entry of several enveloped viruses into their host cells, e.g. HIV, hepatitis C virus and Newcastle disease virus. Labile disulfide bonds are also important in platelet activation, cytokine signalling and in a variety of diseases including cancer and arthritis. In this review we will concentrate on recent advances in understanding the conditions that lead to disulfide bond reduction in membrane proteins and their effects in regulating immune function. Keywords: Disulfide redox · Immunoregulation · Membrane protein · Virus fusion Labile disulfide bonds A role in regulating membrane protein functionCysteine is a unique aa in that it contains a sulfydryl group (-SH) that can covalently bond with a sulfydryl group of a separate cysteine residue to form a disulfide bond. Disulfide bonds can form between cysteines within the same polypeptide chain (intramolecular disulfide bond) or between cysteines on different polypeptide chains (intermolecular disulfide bond). The formation of disulfide bonds requires oxidation of the constituent cysteine residues. Once formed disulfide bonds are not chemically inert, they can be reduced back to their constituent cysteine residues. Although disulfide bonds are clearly important structurally, there is increasing evidence that they can be reduced under certain physiological conditions and that this can affect the activity of the protein itself with downstream functional consequences. In this review we discuss how these redox events may be important in regulating the immune system and we review recent data on the Correspondence: Dr. A. Neil Barclay e-mail: neil.barclay@path.ox.ac.uk characterisation of membrane proteins that contain labile disulfide bonds. Structure and modificationThe disulfide bonds formed between cysteine residues in proteins play an important structural role such as stabilising Ig-like domains in the harsh extracellular environment by bridging the beta sheets at the core of the fold, stabilising dimer formation for example, bridging between the light and heavy chains of Ig. Some disulfide bonds have a catalytic role notably in thioredoxin and protein disulfide isomerases (PDIs). In addition other disulfide bonds can be reduced and these can lead to changes in protein structure and have been termed 'allosteric'. The disulfide bonds themselves are heterogeneous in geometry and this is discussed in detail by Schmidt et al. [1] who studied the geometry of about 7000 disulfide bonds from known structures. In this review we use term labile to describe those disulfide bonds that can be reduced under physiological conditions. It seems likely that they will cause conformational changes but, in the absence of such data, we use the simple term 'labile' meanin...

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Extracellular redox modulation by regulatory T cells

Cited by 130 publications

References 25 publications

Redox Remodeling by Dendritic Cells Protects Antigen-Specific T Cells against Oxidative Stress

Redox Remodeling by Dendritic Cells Protects Antigen-Specific T Cells against Oxidative Stress

Redox outside the Box: Linking Extracellular Redox Remodeling with Intracellular Redox Metabolism

Immunoregulation through membrane proteins modified by reducing conditions induced by immune reactions

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