Discrete Generation of Superoxide and Hydrogen Peroxide by T Cell Receptor Stimulation

Devadas, Satish; Zaritskaya, Luba; Rhee, Sue Goo; Oberley, Larry W.; Williams, Mark S.

doi:10.1084/jem.20010659

Cited by 417 publications

(161 citation statements)

References 58 publications

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“…Recently, two reports have shown that antioxidants can prevent Fas-driven activation-induced cell death (38,39). In both of these reports, the effect of the antioxidant was to inhibit Fas ligand up-regulation after TCR stimulation.…”

Section: Discussionmentioning

confidence: 99%

Control ofBcl-2expression by reactive oxygen species

Hildeman

Mitchell

Aronow

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

235

169

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Reactive oxygen species (ROS) are known to regulate cell death in a variety of cell types. Differential effects of ROS on cell death are observed depending on the level of ROS within the cell (1). High levels of ROS can lead to lipid peroxidation, damage to cellular membranes, inactivation of caspase enzymes, and necrotic cell death (1). In contrast, low levels of ROS have been shown to activate protein kinases and phosphatases, mobilize Ca 2ϩ stores, activate or inactivate transcription factors, and lead to apoptotic cell death (1). Thus, high levels of ROS probably kill cells by means of direct damage, whereas low levels of ROS probably mediate apoptosis indirectly through their effects on protein kinases and͞or phosphatases, transcription factors, and the subsequent effects of these molecules on gene expression. However, little has been done to assess the extent to which ROS affect gene expression in cells undergoing apoptosis.It has been known for some time that Bcl-2 overexpression can protect cells from apoptosis mediated by ROS (2). However, the mechanism by which Bcl-2 prevents ROS-induced apoptosis is unknown. Bcl-2 itself does not possess antioxidant activity; rather, it may act indirectly to increase the levels and͞or activities of endogenous antioxidants (e.g., glutathione or superoxide dismutase) within cells (3-5). Thus, overexpression of Bcl-2 may allow cells to cope better with the effects of ROS, possibly by allowing increases in endogenous antioxidant enzymes.An alternative but not mutually exclusive hypothesis is that ROS act to down-regulate endogenous Bcl-2 levels within cells. Because levels of Bcl-2 within cells are critical to antiapoptotic activity, decreasing Bcl-2 could be a mechanism to sensitize cells to apoptosis. By detoxifying ROS, antioxidants may therefore reverse the ROS-induced decline in Bcl-2 and prevent apoptosis. Several studies suggest a reciprocal relationship between ROS and Bcl-2 levels within cells (6-8). Thus, in divergent cell types, decreases in ROS correlate with increases in Bcl-2 levels and vice versa.Recently we showed that, in vivo, activated T cells decrease their levels of Bcl-2 and become susceptible to the proapoptotic effects of Bim (9). We also showed that culture of these activated T cells with a synthetic catalytic antioxidant, Mn(III) tetrakis(5,10,15,20-benzoic acid)porphyrin (MnTBAP), lowered superoxide levels and prevented apoptosis (10). Here, we show that culture of T cells with MnTBAP reverses the decline in Bcl-2. The corollary of this finding is that ROS are responsible for Bcl-2 down-regulation within activated T cells. Taken together, these results suggest a ''twosignal'' model for activated T cell apoptosis. The first signal is driven by ROS down-regulation of Bcl-2, which is necessary, but not sufficient, to complete apoptosis. The second signal requires the expression of Bim. . RNA extraction, cDNA synthesis, and gene microarray analysis were performed as described (11,12) Mice. C57BL͞10 and C57BL͞6J (BL͞6) mice were purchased from The Ja...

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Section: Discussionmentioning

confidence: 99%

Control ofBcl-2expression by reactive oxygen species

Hildeman

Mitchell

Aronow

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

235

169

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“…In the spleen, Nox5 message localizes to the mantle zone surrounding germinal centers (areas rich in B cells) and to periarterial lymphoid sheets (where mostly T cells are present) (9). T and B lymphocytes produce ROS when stimulated by some receptor agonists (40,41). A role for Nox5 in cell proliferation was suggested by Brar et al (42), who demonstrated that antisense oligonucleotide-mediated down-regulation of Nox5 expression in DU 145 prostate cancer cells inhibits cell proliferation.…”

Section: Nad(p)h Oxidase 5 (Nox5)mentioning

confidence: 98%

The Nox Family of NAD(P)H Oxidases: Host Defense and Beyond

Geiszt

Leto

2004

Journal of Biological Chemistry

408

328

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“…from mitochondria as a metabolic by-product and from enzymes such as NADPH oxidase, which produce ROS essential for cell signaling (21,22). Levels of ROS increase from both these sources on activation and are required for proliferation and differentiation of naïve cells into effector cells: by contrast, the absence of ROS from either source reduces cytokine secretion and proliferation (22,46,47). It is likely that a major source of ROS generated in NK cells by receptor ligation derives from mitochondria, as indicated by the cytoprotective effect of the superoxide dismutase mimetic, MnTBAP (Fig.…”

Section: Discussionmentioning

confidence: 99%

A Novel Serpin Regulatory Mechanism

Mangan

Bird

Kaiserman

et al. 2016

Journal of Biological Chemistry

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The intracellular protease inhibitor Sb9 (SerpinB9) is a regulator of the cytotoxic lymphocyte protease GzmB (granzyme B). Although GzmB is primarily involved in the destruction of compromised cells, recent evidence suggests that it is also involved in lysosome-mediated death of the cytotoxic lymphocyte itself. Sb9 protects the cell from GzmB released from lysosomes into the cytosol. Here we show that reactive oxygen species (ROS) generated within cytotoxic lymphocytes by receptor stimulation are required for lyososomal permeabilization and release of GzmB into the cytosol. Importantly, ROS also inactivate Sb9 by oxidizing a highly conserved cysteine pair (P1-P1 in rodents and P1-P2 in other mammals) in the reactive center loop to form a vicinal disulfide bond. Replacement of the P4-P3 reactive center loop residues of the prototype serpin, SERPINA1, with the P4-P5 residues of Sb9 containing the cysteine pair is sufficient to convert SERPINA1 into a ROS-sensitive GzmB inhibitor. Conversion of the cysteine pair to serines in either human or mouse Sb9 results in a functional serpin that inhibits GzmB and resists ROS inactivation. We conclude that ROS sensitivity of Sb9 allows the threshold for GzmB-mediated suicide to be lowered, as part of a conserved post-translational homeostatic mechanism regulating lymphocyte numbers or activity. It follows, for example, that antioxidants may improve NK cell viability in adoptive immunotherapy applications by stabilizing Sb9.

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Discrete Generation of Superoxide and Hydrogen Peroxide by T Cell Receptor Stimulation

Cited by 417 publications

References 58 publications

Control ofBcl-2expression by reactive oxygen species

Control ofBcl-2expression by reactive oxygen species

The Nox Family of NAD(P)H Oxidases: Host Defense and Beyond

A Novel Serpin Regulatory Mechanism

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