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BASIC IMMUNOLOGY

Reactive Oxygen Species in the Immune System

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Pages 249-270 | Accepted 29 Nov 2012, Published online: 25 Apr 2013

REFERENCES

  • Liou GY, Storz P. Reactive oxygen species in cancer. Free Radic Res 2010;44(5):479–496.
  • Freinbichler W, Colivicchi MA, Stefanini C, Highly reactive oxygen species: detection, formation, and possible functions. Cell Mol Life Sci 2011;68(12):2067–2079.
  • Droge W. Free radicals in the physiological control of cell function. Physiol Rev 2002;82(1):47–95.
  • Reth M. Hydrogen peroxide as second messenger in lymphocyte activation. Nat Immunol 2002;3(12):1129–1134.
  • Finkel T. Signal transduction by reactive oxygen species. J Cell Biol 2011;194(1):7–15.
  • Lee SR, Yang KS, Kwon J, et al. Reversible inactivation of the tumor suppressor PTEN by H2O2. J Biol Chem 2002;277(23):20336–20342.
  • Chan DW, Liu VW, Tsao GS, Loss of MKP3 mediated by oxidative stress enhances tumorigenicity and chemoresistance of ovarian cancer cells. Carcinogenesis 2008;29(9):1742–1750.
  • Miller EW, Dickinson BC, Chang CJ. Aquaporin-3 mediates hydrogen peroxide uptake to regulate downstream intracellular signaling. Proc Natl Acad Sci USA 2010;107(36):15681–15686.
  • Woo HA, Yim SH, Shin DH, et al. Inactivation of peroxiredoxin I by phosphorylation allows localized H(2)O(2) accumulation for cell signaling. Cell 2010;140(4):517–528.
  • Saitoh M, Nishitoh H, Fujii M, Mammalian thioredoxin is a direct inhibitor of apoptosis signal-regulating kinase (ASK) 1. EMBO J 1998;17(9):2596–2606.
  • Zhou R, Tardivel A, Thorens B, Thioredoxin-interacting protein links oxidative stress to inflammasome activation. Nat Immunol 2010;11(2):136–140.
  • Funato Y, Michiue T, Asashima M, Miki H. The thioredoxin-related redox-regulating protein nucleoredoxin inhibits Wnt-beta-catenin signalling through dishevelled. Nat Cell Biol 2006;8(5):501–508.
  • Kim YJ, Lee WS, Ip C, et al. Prx1 suppresses radiation-induced c-Jun NH2-terminal kinase signaling in lung cancer cells through interaction with the glutathione S-transferase Pi/c-Jun NH2-terminal kinase complex. Cancer Res 2006;66(14):7136–7142.
  • Rutault K, Alderman C, Chain BM, Katz DR. Reactive oxygen species activate human peripheral blood dendritic cells. Free Radic Biol Med 1999;26(1–2):232–238.
  • Schmielau J, Finn OJ. Activated granulocytes and granulocyte-derived hydrogen peroxide are the underlying mechanism of suppression of t-cell function in advanced cancer patients. Cancer Res 2001;61(12):4756–4760.
  • Malmberg KJ, Arulampalam V, Ichihara F, Inhibition of activated/memory (CD45RO(+)) T cells by oxidative stress associated with block of NF-kappaB activation. J Immunol 2001;167(5):2595–2601.
  • Li W, Lidebjer C, Yuan XM, NK cell apoptosis in coronary artery disease: relation to oxidative stress. Atherosclerosis 2008;199(1):65–72.
  • Babior BM, Kipnes RS, Curnutte JT. Biological defense mechanisms. The production by leukocytes of superoxide, a potential bactericidal agent. J Clin Invest 1973;52(3):741–744.
  • Babior BM. The respiratory burst of phagocytes. J Clin Invest 1984;73(3):599–601.
  • Lam GY, Huang J, Brumell JH. The many roles of NOX2 NADPH oxidase-derived ROS in immunity. Semin Immunopathol 2010;32(4):415–430.
  • Nauseef WM. Nox enzymes in immune cells. Semin Immunopathol 2008;30(3):195–208.
  • Lambeth JD. NOX enzymes and the biology of reactive oxygen. Nat Rev Immunol 2004;4(3):181–189.
  • Sareila O, Kelkka T, Pizzolla A, NOX2 complex-derived ROS as immune regulators. Antioxid Redox Signal 2011;15(8):2197–2208.
  • Segal AW. The NADPH oxidase and chronic granulomatous disease. Mol Med Today 1996;2(3):129–135.
  • Roos D, van Bruggen R, Meischl C. Oxidative killing of microbes by neutrophils. Microbes Infect 2003;5(14):1307–1315.
  • Haas A, Goebel W. Microbial strategies to prevent oxygen-dependent killing by phagocytes. Free Radic Res Commun 1992;16(3):137–157.
  • Reeves EP, Lu H, Jacobs HL, Killing activity of neutrophils is mediated through activation of proteases by K+ flux. Nature 2002;416(6878):291–297.
  • Segal AW. How neutrophils kill microbes. Annu Rev Immunol 2005;23:197–223.
  • Brinkmann V, Reichard U, Goosmann C, Neutrophil extracellular traps kill bacteria. Science 2004;303(5663):1532–1535.
  • Wartha F, Henriques-Normark B. ETosis: a novel cell death pathway. Sci Signal 2008;1(21):pe25.
  • Amulic B, Hayes G. Neutrophil extracellular traps. Curr Biol 2011;21(9):R297–R298.
  • Bianchi M, Hakkim A, Brinkmann V, Restoration of NET formation by gene therapy in CGD controls aspergillosis. Blood 2009;114(13):2619–2622.
  • Dikalov S. Cross talk between mitochondria and NADPH oxidases. Free Radic Biol Med 2011;51(7):1289–1301.
  • Gross O, Thomas CJ, Guarda G, Tschopp J. The inflammasome: an integrated view. Immunol Rev 2011;243(1):136–151.
  • Strowig T, Henao-Mejia J, Elinav E, Flavell R. Inflammasomes in health and disease. Nature 2012;481(7381):278–286.
  • Franchi L, Munoz-Planillo R, Nunez G. Sensing and reacting to microbes through the inflammasomes. Nat Immunol 2012;13(4):325–332.
  • Tschopp J, Schroder K. NLRP3 inflammasome activation: the convergence of multiple signalling pathways on ROS production? Nat Rev Immunol 2010;10(3):210–215.
  • Dostert C, Petrilli V, Van Bruggen R, Innate immune activation through Nalp3 inflammasome sensing of asbestos and silica. Science 2008;320(5876):674–677.
  • Petrilli V, Papin S, Dostert C, Activation of the NALP3 inflammasome is triggered by low intracellular potassium concentration. Cell Death Differ 2007;14(9):1583–1589.
  • Masters SL, Dunne A, Subramanian SL, Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1beta in type 2 diabetes. Nat Immunol 2010;11(10):897–904.
  • Cruz CM, Rinna A, Forman HJ, ATP activates a reactive oxygen species-dependent oxidative stress response and secretion of proinflammatory cytokines in macrophages. J Biol Chem 2007;282(5):2871–2879.
  • Hornung V, Bauernfeind F, Halle A, Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nat Immunol 2008;9(8):847–856.
  • van de Veerdonk FL, Smeekens SP, Joosten LA, Reactive oxygen species-independent activation of the IL-1beta inflammasome in cells from patients with chronic granulomatous disease. Proc Natl Acad Sci USA 2010;107(7):3030–3033.
  • Nakahira K, Haspel JA, Rathinam VA, Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat Immunol 2011;12(3):222–230.
  • Zhou R, Yazdi AS, Menu P, Tschopp J. A role for mitochondria in NLRP3 inflammasome activation. Nature 2011;469(7329):221–225.
  • Naik E, Dixit VM. Mitochondrial reactive oxygen species drive proinflammatory cytokine production. J Exp Med 2011;208(3):417–420.
  • Bulua AC, Simon A, Maddipati R, Mitochondrial reactive oxygen species promote production of proinflammatory cytokines and are elevated in TNFR1-associated periodic syndrome (TRAPS). J Exp Med 2011;208(3):519–533.
  • Veal EA, Day AM, Morgan BA. Hydrogen peroxide sensing and signaling. Mol Cell 2007;26(1):1–14.
  • West AP, Shadel GS, Ghosh S. Mitochondria in innate immune responses. Nat Rev Immunol 2011;11(6):389–402.
  • Koshiba T. Mitochondrial-mediated antiviral immunity. Biochim Biophys Acta 2013;1833(1):225–232.
  • West AP, Brodsky IE, Rahner C, TLR signalling augments macrophage bactericidal activity through mitochondrial ROS. Nature 2011;472(7344):476–480.
  • Dalton DK, Pitts-Meek S, Keshav S, Multiple defects of immune cell function in mice with disrupted interferon-gamma genes. Science 1993;259(5102):1739–1742.
  • Sonoda J, Laganiere J, Mehl IR, Nuclear receptor ERR alpha and coactivator PGC-1 beta are effectors of IFN-gamma-induced host defense. Genes Dev 2007;21(15):1909–1920.
  • Vats D, Mukundan L, Odegaard JI, Oxidative metabolism and PGC-1beta attenuate macrophage-mediated inflammation. Cell Metab 2006;4(1):13–24.
  • Loo YM, Gale M, Jr. Immune signaling by RIG-I-like receptors. Immunity 2011;34(5):680–692.
  • Seth RB, Sun L, Ea CK, Chen ZJ. Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-kappaB and IRF 3. Cell 2005;122(5):669–682.
  • Kawai T, Takahashi K, Sato S, IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction. Nat Immunol 2005;6(10):981–988.
  • Meylan E, Curran J, Hofmann K, Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus. Nature 2005;437(7062):1167–1172.
  • Xu LG, Wang YY, Han KJ, VISA is an adapter protein required for virus-triggered IFN-beta signaling. Mol Cell 2005;19(6):727–740.
  • Tal MC, Sasai M, Lee HK, et al. Absence of autophagy results in reactive oxygen species-dependent amplification of RLR signaling. Proc Natl Acad Sci USA 2009;106(8):2770–2775.
  • Soucy-Faulkner A, Mukawera E, Fink K, Requirement of NOX2 and reactive oxygen species for efficient RIG-I-mediated antiviral response through regulation of MAVS expression. PLoS Pathog 2010;6(6):e1000930.
  • Doughan AK, Harrison DG, Dikalov SI. Molecular mechanisms of angiotensin II-mediated mitochondrial dysfunction: linking mitochondrial oxidative damage and vascular endothelial dysfunction. Circ Res 2008;102(4):488–496.
  • Dikalova AE, Bikineyeva AT, Budzyn K, Therapeutic targeting of mitochondrial superoxide in hypertension. Circ Res 2010;107(1):106–116.
  • Daiber A. Redox signaling (cross-talk) from and to mitochondria involves mitochondrial pores and reactive oxygen species. Biochim Biophys Acta 2010;1797(6–7):897–906.
  • Malhotra A, Shanker A. NK cells: immune cross-talk and therapeutic implications. Immunotherapy 2011;3(10):1143–66.
  • Roder JC, Helfand SL, Werkmeister J, Oxygen intermediates are triggered early in the cytolytic pathway of human NK cells. Nature 1982;298(5874):569–572.
  • Duwe AK, Roder JC. Involvement of hydroxyl free radical, but not superoxide, in the cytolytic pathway of natural killer cells. Revision of an earlier hypothesis. Med Biol 1984;62(2):95–100.
  • Duwe AK, Werkmeister J, Roder JC, Natural killer cell-mediated lysis involves an hydroxyl radical-dependent step. J Immunol 1985;134(4):2637–2644.
  • Suthanthiran M, Solomon SD, Williams PS, Hydroxyl radical scavengers inhibit human natural killer cell activity. Nature 1984;307(5948):276–278.
  • Kay HD, Smith DL, Sullivan G, Evidence for a nonoxidative mechanism of human natural killer (NK) cell cytotoxicity by using mononuclear effector cells from healthy donors and from patients with chronic granulomatous disease. J Immunol 1983;131(4):1784–1788.
  • Ramstedt U, Rossi P, Kullman C, Free oxygen radicals are not detectable by chemiluminescence during human natural killer cell cytotoxicity. Scand J Immunol 1984;19(5):457–464.
  • Storkus WJ, Dawson JR. Oxygen-reactive metabolites are not detected at the effector-target interface during natural killing. J Leukoc Biol 1986;39(5):547–557.
  • Gibboney JJ, Haak RA, Kleinhans FW, Brahmi Z. Electron spin resonance spectroscopy does not reveal hydroxyl radical production in activated natural killer lymphocytes. J Leukoc Biol 1988;44(6):545–550.
  • Hansson M, Romero A, Thoren F, Activation of cytotoxic lymphocytes by interferon-alpha: role of oxygen radical-producing mononuclear phagocytes. J Leukoc Biol 2004;76(6):1207–1213.
  • Hellstrand K, Asea A, Dahlgren C, Hermodsson S. Histaminergic regulation of NK cells. Role of monocyte-derived reactive oxygen metabolites. J Immunol 1994;153(11):4940–4947.
  • Asea A, Hansson M, Czerkinsky C, Histaminergic regulation of interferon-gamma (IFN-gamma) production by human natural killer (NK) cells. Clin Exp Immunol 1996;105(2):376–382.
  • Seaman WE, Gindhart TD, Blackman MA, Suppression of natural killing in vitro by monocytes and polymorphonuclear leukocytes: requirement for reactive metabolites of oxygen. J Clin Invest 1982;69(4):876–888.
  • Kono K, Salazar-Onfray F, Petersson M, Hydrogen peroxide secreted by tumor-derived macrophages down-modulates signal-transducing zeta molecules and inhibits tumor-specific T cell-and natural killer cell-mediated cytotoxicity. Eur J Immunol 1996;26(6):1308–1313.
  • Corsi MM, Maes HH, Wasserman K, Protection by L-2-oxothiazolidine-4-carboxylic acid of hydrogen peroxide-induced CD3zeta and CD16zeta chain down-regulation in human peripheral blood lymphocytes and lymphokine-activated killer cells. Biochem Pharmacol 1998;56(5):657–662.
  • Brune M, Hansson M, Mellqvist UH, NK cell-mediated killing of AML blasts: role of histamine, monocytes and reactive oxygen metabolites. Eur J Haematol 1996;57(4):312–319.
  • Houze TA, Larsson PA, Hellstrand K, Gustavsson B. The role of reactive oxygen metabolites in the transcriptional regulation of IFN-gamma gene expression by histamine in NK cells following IL-2 stimulation. Cell Biol Int 1996;20(9):589–598.
  • Asea A, Hermodsson S, Hellstrand K. Histaminergic regulation of natural killer cell-mediated clearance of tumour cells in mice. Scand J Immunol 1996;43(1):9–15.
  • Brune M, Castaigne S, Catalano J, Improved leukemia-free survival after postconsolidation immunotherapy with histamine dihydrochloride and interleukin-2 in acute myeloid leukemia: results of a randomized phase 3 trial. Blood 2006;108(1):88–96.
  • Hansson M, Asea A, Ersson U, Induction of apoptosis in NK cells by monocyte-derived reactive oxygen metabolites. J Immunol 1996;156(1):42–47.
  • Aurelius J, Thoren FB, Akhiani AA, Monocytic AML cells inactivate antileukemic lymphocytes: role of NADPH oxidase/gp91(phox) expression and the PARP-1/PAR pathway of apoptosis. Blood 2012;119(24):5832–5837.
  • Li W, Johnson H, Yuan XM, Jonasson L. 7beta-hydroxycholesterol induces natural killer cell death via oxidative lysosomal destabilization. Free Radic Res 2009;43(11):1072–1079.
  • Huang Y, Lei Y, Zhang H, Interleukin-12 treatment down-regulates STAT4 and induces apoptosis with increasing ROS production in human natural killer cells. J Leukoc Biol 2011;90(1): 87–97.
  • Romero AI, Thoren FB, Brune M, Hellstrand K. NKp46 and NKG2D receptor expression in NK cells with CD56dim and CD56bright phenotype: regulation by histamine and reactive oxygen species. Br J Haematol 2006;132(1):91–98.
  • Harlin H, Hanson M, Johansson CC, The CD16- CD56(bright) NK cell subset is resistant to reactive oxygen species produced by activated granulocytes and has higher antioxidative capacity than the CD16+ CD56(dim) subset. J Immunol 2007;179(7):4513–4519.
  • Thoren FB, Romero AI, Hermodsson S, Hellstrand K. The CD16-/CD56bright subset of NK cells is resistant to oxidant-induced cell death. J Immunol 2007;179(2):781–785.
  • Izawa S, Kono K, Mimura K, H(2)O(2) production within tumor microenvironment inversely correlated with infiltration of CD56(dim) NK cells in gastric and esophageal cancer: possible mechanisms of NK cell dysfunction. Cancer Immunol Immunother 2011;60(12):1801–1810.
  • Del Prete A, Zaccagnino P, Di Paola M, Role of mitochondria and reactive oxygen species in dendritic cell differentiation and functions. Free Radic Biol Med 2008;44(7):1443–1451.
  • Sheng KC, Pietersz GA, Tang CK, Reactive oxygen species level defines two functionally distinctive stages of inflammatory dendritic cell development from mouse bone marrow. J Immunol 2010;184(6):2863–2872.
  • Mellman I, Steinman RM. Dendritic cells: specialized and regulated antigen processing machines. Cell 2001;106(3):255–258.
  • Kantengwa S, Jornot L, Devenoges C, Nicod LP. Superoxide anions induce the maturation of human dendritic cells. Am J Respir Crit Care Med 2003;167(3):431–437.
  • Lahiri A, Das P, Vani J, TLR 9 activation in dendritic cells enhances salmonella killing and antigen presentation via involvement of the reactive oxygen species. PLoS One 2010;5(10):e13772.
  • Ogasawara N, Oguro T, Sakabe T, Hemoglobin induces the expression of indoleamine 2,3-dioxygenase in dendritic cells through the activation of PI3K, PKC, and NF-kappaB and the generation of reactive oxygen species. J Cell Biochem 2009;108(3):716–725.
  • Rock KL, Shen L. Cross-presentation: underlying mechanisms and role in immune surveillance. Immunol Rev 2005;207:166–183.
  • Elsen S, Doussiere J, Villiers CL, Cryptic O2- -generating NADPH oxidase in dendritic cells. J Cell Sci 2004;117(Pt 11):2215–2226.
  • Mantegazza AR, Savina A, Vermeulen M, NADPH oxidase controls phagosomal pH and antigen cross-presentation in human dendritic cells. Blood 2008;112(12):4712–4722.
  • Kotsias F, Hoffmann E, Amigorena S, Savina A. Reactive oxygen species production in the phagosome: impact on antigen presentation in dendritic cells. Antioxid Redox Signal 2012 (September 11) [Epub ahead of print].
  • Savina A, Jancic C, Hugues S, NOX2 controls phagosomal pH to regulate antigen processing during crosspresentation by dendritic cells. Cell 2006;126(1):205–218.
  • Fidelus RK, Ginouves P, Lawrence D, Tsan MF. Modulation of intracellular glutathione concentrations alters lymphocyte activation and proliferation. Exp Cell Res 1987;170(2):269–275.
  • Novogrodsky A, Ravid A, Rubin AL, Stenzel KH. Hydroxyl radical scavengers inhibit lymphocyte mitogenesis. Proc Natl Acad Sci USA 1982;79(4):1171–1174.
  • Chaudhri G, Hunt NH, Clark IA, Ceredig R. Antioxidants inhibit proliferation and cell surface expression of receptors for interleukin-2 and transferrin in T lymphocytes stimulated with phorbol myristate acetate and ionomycin. Cell Immunol 1988;115(1):204–213.
  • Chaudhri G, Clark IA, Hunt NH, Effect of antioxidants on primary alloantigen-induced T cell activation and proliferation. J Immunol 1986;137(8):2646–2652.
  • Williams MS, Kwon J. T cell receptor stimulation, reactive oxygen species, and cell signaling. Free Radic Biol Med 2004;37(8):1144–1151.
  • Devadas S, Zaritskaya L, Rhee SG, Discrete generation of superoxide and hydrogen peroxide by T cell receptor stimulation: selective regulation of mitogen-activated protein kinase activation and fas ligand expression. J Exp Med 2002;195(1):59–70.
  • Jackson SH, Devadas S, Kwon J, T cells express a phagocyte-type NADPH oxidase that is activated after T cell receptor stimulation. Nat Immunol 2004;5(8):818–827.
  • Kwon J, Devadas S, Williams MS. T cell receptor-stimulated generation of hydrogen peroxide inhibits MEK-ERK activation and lck serine phosphorylation. Free Radic Biol Med 2003;35(4):406–417.
  • Kaminski MM, Sauer SW, Klemke CD, Mitochondrial reactive oxygen species control T cell activation by regulating IL-2 and IL-4 expression: mechanism of ciprofloxacin-mediated immunosuppression. J Immunol 2010;184(9):4827–4841.
  • Yi JS, Holbrook BC, Michalek RD, Electron transport complex I is required for CD8+ T cell function. J Immunol 2006;177(2):852–862.
  • Kaminski M, Kiessling M, Suss D, Novel role for mitochondria: protein kinase Ctheta-dependent oxidative signaling organelles in activation-induced T-cell death. Mol Cell Biol 2007;27(10):3625–3639.
  • Gelderman KA, Hultqvist M, Pizzolla A, Macrophages suppress T cell responses and arthritis development in mice by producing reactive oxygen species. J Clin Invest 2007;117(10):3020–3028.
  • Matsue H, Edelbaum D, Shalhevet D, Generation and function of reactive oxygen species in dendritic cells during antigen presentation. J Immunol 2003;171(6):3010–3018.
  • Fooksman DR, Vardhana S, Vasiliver-Shamis G, Functional anatomy of T cell activation and synapse formation. Annu Rev Immunol 2010;28:79–105.
  • Hultqvist M, Olsson LM, Gelderman KA, Holmdahl R. The protective role of ROS in autoimmune disease. Trends Immunol 2009;30(5):201–208.
  • Case AJ, McGill JL, Tygrett LT, Elevated mitochondrial superoxide disrupts normal T cell development, impairing adaptive immune responses to an influenza challenge. Free Radic Biol Med 2011;50(3):448–458.
  • Lahdenpohja N, Savinainen K, Hurme M. Pre-exposure to oxidative stress decreases the nuclear factor-kappa B-dependent transcription in T lymphocytes. J Immunol 1998;160(3):1354–1358.
  • Tripathi P, Hildeman D. Sensitization of T cells to apoptosis–a role for ROS? Apoptosis 2004;9(5):515–523.
  • Diebold SS. Determination of T-cell fate by dendritic cells. Immunol Cell Biol 2008;86(5):389–397.
  • Krueger A, Fas SC, Baumann S, Krammer PH. The role of CD95 in the regulation of peripheral T-cell apoptosis. Immunol Rev 2003;193:58–69.
  • Green DR, Droin N, Pinkoski M. Activation-induced cell death in T cells. Immunol Rev 2003;193:70–81.
  • Hildeman DA. Regulation of T-cell apoptosis by reactive oxygen species. Free Radic Biol Med 2004;36(12):1496–1504.
  • Li-Weber M, Krammer PH. The death of a T-cell: expression of the CD95 ligand. Cell Death Differ 2002;9(2):101–103.
  • Bauer MK, Vogt M, Los M, et al. Role of reactive oxygen intermediates in activation-induced CD95 (APO-1/Fas) ligand expression. J Biol Chem 1998;273(14):8048–8055.
  • Li-Weber M, Weigand MA, Giaisi M, Vitamin E inhibits CD95 ligand expression and protects T cells from activation-induced cell death. J Clin Invest 2002;110(5):681–690.
  • Zhang N, Hartig H, Dzhagalov I, The role of apoptosis in the development and function of T lymphocytes. Cell Res 2005;15(10):749–769.
  • Martinou JC, Youle RJ. Mitochondria in apoptosis: Bcl-2 family members and mitochondrial dynamics. Dev Cell 2011;21(1):92–101.
  • Kroemer G, Galluzzi L, Brenner C. Mitochondrial membrane permeabilization in cell death. Physiol Rev 2007;87(1):99–163.
  • Ott M, Robertson JD, Gogvadze V, Cytochrome c release from mitochondria proceeds by a two-step process. Proc Natl Acad Sci USA 2002;99(3):1259–1263.
  • Cheng EH, Wei MC, Weiler S, BCL-2, BCL-X(L) sequester BH3 domain-only molecules preventing BAX- and BAK-mediated mitochondrial apoptosis. Mol Cell 2001;8(3):705–711.
  • Hildeman DA, Zhu Y, Mitchell TC, Activated T cell death in vivo mediated by proapoptotic bcl-2 family member bim. Immunity 2002;16(6):759–767.
  • Orrenius S, Gogvadze V, Zhivotovsky B. Mitochondrial oxidative stress: implications for cell death. Annu Rev Pharmacol Toxicol 2007;47:143–83.
  • Vene R, Delfino L, Castellani P, Redox remodeling allows and controls B-cell activation and differentiation. Antioxid Redox Signal 2010;13(8):1145–1155.
  • Bertolotti M, Yim SH, Garcia-Manteiga JM, B- to plasma-cell terminal differentiation entails oxidative stress and profound reshaping of the antioxidant responses. Antioxid Redox Signal 2010;13(8):1133–1144.
  • Yang Y, Karakhanova S, Soltek S, In vivo immunoregulatory properties of the novel mitochondria-targeted antioxidant SkQ1. Mol Immunol 2012;52(1):19–29.
  • Wentworth AD, Jones LH, Wentworth P, Jr., et al. Antibodies have the intrinsic capacity to destroy antigens. Proc Natl Acad Sci USA 2000;97(20):10930–10935.
  • Berlett BS, Stadtman ER. Protein oxidation in aging, disease, and oxidative stress. J Biol Chem 1997;272(33):20313–20316.
  • Sheikh Z, Ahmad R, Sheikh N, Ali R. Enhanced recognition of reactive oxygen species damaged human serum albumin by circulating systemic lupus erythematosus autoantibodies. Autoimmunity 2007;40(7):512–520.
  • Chiang CL, Ledermann JA, Aitkens E, Oxidation of ovarian epithelial cancer cells by hypochlorous acid enhances immunogenicity and stimulates T cells that recognize autologous primary tumor. Clin Cancer Res 2008;14(15):4898–4907.
  • Weiskopf D, Schwanninger A, Weinberger B, Oxidative stress can alter the antigenicity of immunodominant peptides. J Leukoc Biol 2010;87(1):165–172.
  • Vignali DA, Collison LW, Workman CJ. How regulatory T cells work. Nat Rev Immunol 2008;8(7):523–532.
  • Efimova O, Szankasi P, Kelley TW. Ncf1 (p47phox) is essential for direct regulatory T cell mediated suppression of CD4+ effector T cells. PLoS One 2011;6(1):e16013.
  • Lahdenpohja N, Hurme M. Naive (CD45RA+) T lymphocytes are more sensitive to oxidative stress-induced signals than memory (CD45RO+) cells. Cell Immunol 1996;173(2):282–286.
  • Takahashi A, Hanson MG, Norell HR, Preferential cell death of CD8 +effector memory (CCR7-CD45RA-) T cells by hydrogen peroxide-induced oxidative stress. J Immunol 2005;174(10):6080–6087.
  • Gupta S, Young T, Yel L, Differential sensitivity of naive and subsets of memory CD4+ and CD8+ T cells to hydrogen peroxide-induced apoptosis. Genes Immun 2007;8(7):560–569.
  • Mougiakakos D, Johansson CC, Kiessling R. Naturally occurring regulatory T cells show reduced sensitivity toward oxidative stress-induced cell death. Blood 2009;113(15):3542–3545.
  • Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol 2009;9(3):162–174.
  • Whiteside TL. The tumor microenvironment and its role in promoting tumor growth. Oncogene 2008;27(45):5904–5912.
  • Condamine T, Gabrilovich DI. Molecular mechanisms regulating myeloid-derived suppressor cell differentiation and function. Trends Immunol 2011;32(1):19–25.
  • Gabrilovich DI, Ostrand-Rosenberg S, Bronte V. Coordinated regulation of myeloid cells by tumours. Nat Rev Immunol 2012;12(4):253–268.
  • Cheng P, Corzo CA, Luetteke N, Inhibition of dendritic cell differentiation and accumulation of myeloid-derived suppressor cells in cancer is regulated by S100A9 protein. J Exp Med 2008;205(10):2235–2249.
  • Gorlin RJ, Koutlas IG. Multiple schwannomas, multiple nevi, and multiple vaginal leiomyomas: a new dominant syndrome. Am J Med Genet 1998;78(1):76–81.
  • Jia W, Jackson-Cook C, Graf MR. Tumor-infiltrating, myeloid-derived suppressor cells inhibit T cell activity by nitric oxide production in an intracranial rat glioma + vaccination model. J Neuroimmunol 2010;223(1–2):20–30.
  • Harari O, Liao JK. Inhibition of MHC II gene transcription by nitric oxide and antioxidants. Curr Pharm Des 2004;10(8):893–898.
  • Kusmartsev S, Nefedova Y, Yoder D, Gabrilovich DI. Antigen-specific inhibition of CD8+ T cell response by immature myeloid cells in cancer is mediated by reactive oxygen species. J Immunol 2004;172(2):989–999.
  • Nagaraj S, Gupta K, Pisarev V, Altered recognition of antigen is a mechanism of CD8+ T cell tolerance in cancer. Nat Med 2007;13(7):828–835.
  • Kraaij MD, Savage ND, van der Kooij SW, Induction of regulatory T cells by macrophages is dependent on production of reactive oxygen species. Proc Natl Acad Sci USA 2010;107(41):17686–17691.
  • Centuori SM, Trad M, Lacasse CJ, Myeloid-derived suppressor cells from tumor-bearing mice impair TGF-beta-induced differentiation of CD4+CD25+FoxP3+ Tregs from CD4+CD25-FoxP3- T cells. J Leukoc Biol 2012;92(5):987–997.

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