Cited by 214Redox biology and oxidative stressT-cell and B-cell ImmunologyNeutrophil, Myeloperoxidase and Oxidative Mechanisms

The Role of Reactive Oxygen Species in Regulating T Cell-mediated Immunity and Disease

Open access
Yarosz, Emily L., Chang, Cheong-Hee·2018·Immune Network

Abstract

T lymphocytes rely on several metabolic processes to produce the high amounts of energy and metabolites needed to drive clonal expansion and the development of effector functions. However, many of these pathways result in the production of reactive oxygen species (ROS), which have canonically been thought of as cytotoxic agents due to their ability to damage DNA and other subcellular structures. Interestingly, ROS has recently emerged as a critical second messenger for T cell receptor signaling and T cell activation, but the sensitivity of different T cell subsets to ROS varies. Therefore, the tight regulation of ROS production by cellular antioxidant pathways is critical to maintaining proper signal transduction without compromising the integrity of the cell. This review intends to detail the common metabolic sources of intracellular ROS and the mechanisms by which ROS contributes to the development of T cell-mediated immunity. The regulation of ROS levels by the glutathione pathway and the Nrf2-Keap1-Cul3 trimeric complex will be discussed. Finally, T cell-mediated autoimmune diseases exacerbated by defects in ROS regulation will be further examined in order to identify potential therapeutic interventions for these disorders.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.4110/in.2018.18.e14

Cites

8 of 8 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 64

  1. [1]Ray PD Huang BW Tsuji Y Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signaling Cell Signal 2012 24 981 990 22286106 PMC3454471
  2. [2]Bulua AC Simon A Maddipati R Pelletier M Park H Kim KY Sack MN Kastner DL Siegel RM Mitochondrial reactive oxygen species promote production of proinflammatory cytokines and are elevated in TNFR1-associated periodic syndrome (TRAPS) J Exp Med 2011 208 519 533 21282379 PMC3058571
  3. [3]Byun HO Kim HY Lim JJ Seo YH Yoon G Mitochondrial dysfunction by complex II inhibition delays overall cell cycle progression via reactive oxygen species production J Cell Biochem 2008 104 1747 1759 18395845
  4. [4]Tormos KV Anso E Hamanaka RB Eisenbart J Joseph J Kalyanaraman B Chandel NS Mitochondrial complex III ROS regulate adipocyte differentiation Cell Metab 2011 14 537 544 21982713 PMC3190168
  5. [6]Imboden JB Stobo JD Transmembrane signalling by the T cell antigen receptor. Perturbation of the T3-antigen receptor complex generates inositol phosphates and releases calcium ions from intracellular stores J Exp Med 1985 161 446 456 3919143 PMC2187575
  6. [7]Murphy AN Fiskum G Beal MF Mitochondria in neurodegeneration: bioenergetic function in cell life and death J Cereb Blood Flow Metab 1999 19 231 245 10078875
  7. [8]Loschen G Azzi A Flohe L Mitochondrial H2O2 formation: relationship with energy conservation FEBS Lett 1973 33 84 87 4737333
  8. [9]Turrens JF Freeman BA Levitt JG Crapo JD The effect of hyperoxia on superoxide production by lung submitochondrial particles Arch Biochem Biophys 1982 217 401 410 6291460
  9. [10]Nohl H Gille L Schonheit K Liu Y Conditions allowing redox-cycling ubisemiquinone in mitochondria to establish a direct redox couple with molecular oxygen Free Radic Biol Med 1996 20 207 213 8746441
  10. [11]Phaniendra A Jestadi DB Periyasamy L Free radicals: properties, sources, targets, and their implication in various diseases Indian J Clin Biochem 2015 30 11 26 25646037 PMC4310837
  11. [12]Turrens JF Boveris A Generation of superoxide anion by the NADH dehydrogenase of bovine heart mitochondria Biochem J 1980 191 421 427 6263247 PMC1162232
  12. [13]Lenaz G The mitochondrial production of reactive oxygen species: mechanisms and implications in human pathology IUBMB Life 2001 52 159 164 11798028
  13. [14]Turrens JF Alexandre A Lehninger AL Ubisemiquinone is the electron donor for superoxide formation by complex III of heart mitochondria Arch Biochem Biophys 1985 237 408 414 2983613
  14. [15]Fisher-Wellman KH Gilliam LA Lin CT Cathey BL Lark DS Neufer PD Mitochondrial glutathione depletion reveals a novel role for the pyruvate dehydrogenase complex as a key H2O2-emitting source under conditions of nutrient overload Free Radic Biol Med 2013 65 1201 1208 24056031 PMC3965186
  15. [16]Starkov AA Fiskum G Chinopoulos C Lorenzo BJ Browne SE Patel MS Beal MF Mitochondrial alpha-ketoglutarate dehydrogenase complex generates reactive oxygen species J Neurosci 2004 24 7779 7788 15356189 PMC6729932
  16. [17]Pearce EL Poffenberger MC Chang CH Jones RG Fueling immunity: insights into metabolism and lymphocyte function Science 2013 342 1242454 24115444 PMC4486656
  17. [18]Kamiński MM Sauer SW Kamiński M Opp S Ruppert T Grigaravičius P Grudnik P Gröne HJ Krammer PH Gulow K T cell activation is driven by an ADP-dependent glucokinase linking enhanced glycolysis with mitochondrial reactive oxygen species generation Cell Reports 2012 2 1300 1315 23168256
  18. [19]Sena LA Li S Jairaman A Prakriya M Ezponda T Hildeman DA Wang CR Schumacker PT Licht JD Perlman H Mitochondria are required for antigen-specific T cell activation through reactive oxygen species signaling Immunity 2013 38 225 236 23415911 PMC3582741
  19. [20]Zhu L Yu X Akatsuka Y Cooper JA Anasetti C Role of mitogen-activated protein kinases in activation-induced apoptosis of T cells Immunology 1999 97 26 35 10447711 PMC2326808
  20. [21]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 35 406 417 12899942
  21. [23]Jackson SH Devadas S Kwon J Pinto LA Williams MS T cells express a phagocyte-type NADPH oxidase that is activated after T cell receptor stimulation Nat Immunol 2004 5 818 827 15258578
  22. [24]Kamiński MM Röth D Sass S Sauer SW Krammer PH Gülow K Manganese superoxide dismutase: a regulator of T cell activation-induced oxidative signaling and cell death Biochim Biophys Acta 2012 1823 1041 1052 22429591
  23. [25]Frossi B De Carli M Piemonte M Pucillo C Oxidative microenvironment exerts an opposite regulatory effect on cytokine production by Th1 and Th2 cells Mol Immunol 2008 45 58 64 17588662
  24. [26]Kaminski MM Sauer SW Klemke CD Suss D Okun JG Krammer PH Gulow K 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 4827 4841 20335530
  25. [27]Fu G Xu Q Qiu Y Jin X Xu T Dong S Wang J Ke Y Hu H Cao X Suppression of Th17 cell differentiation by misshapen/NIK-related kinase MINK1 J Exp Med 2017 214 1453 1469 28400474 PMC5413330
  26. [28]Abimannan T Peroumal D Parida JR Barik PK Padhan P Devadas S Oxidative stress modulates the cytokine response of differentiated Th17 and Th1 cells Free Radic Biol Med 2016 99 352 363 27567538
  27. [29]Kim YH Kumar A Chang CH Pyaram K Reactive oxygen species regulate the inflammatory function of NKT cells through promyelocytic leukemia zinc finger J Immunol 2017 199 3478 3487 29021374 PMC5685185
  28. [30]Russell JH Rush B Weaver C Wang R Mature T cells of autoimmune lpr/lpr mice have a defect in antigen-stimulated suicide Proc Natl Acad Sci USA 1993 90 4409 4413 8506280 PMC46520
  29. [31]Waring P Mullbacher A Cell death induced by the Fas/Fas ligand pathway and its role in pathology Immunol Cell Biol 1999 77 312 317 10457197
  30. [32]Lee DH Son DJ Park MH Yoon DY Han SB Hong JT Glutathione peroxidase 1 deficiency attenuates concanavalin A-induced hepatic injury by modulation of T-cell activation Cell Death Dis 2016 7 e2208 27124582 PMC4855674
  31. [33]Bennett SJ Griffiths HR Regulation of T-cell functions by oxidative stress Alcaraz MJ Gualillo O Sánchez-Pernaute O Studies on Arthritis and Joint Disorders New York, NY Humana Press 2013 33 48
  32. [34]Checker R Sharma D Sandur SK Subrahmanyam G Krishnan S Poduval TB Sainis KB Plumbagin inhibits proliferative and inflammatory responses of T cells independent of ROS generation but by modulating intracellular thiols J Cell Biochem 2010 110 1082 1093 20564204 PMC3065107
  33. [35]Hamilos DL Zelarney P Mascali JJ Lymphocyte proliferation in glutathione-depleted lymphocytes: direct relationship between glutathione availability and the proliferative response Immunopharmacology 1989 18 223 235 2575086
  34. [36]Mak TW Grusdat M Duncan GS Dostert C Nonnenmacher Y Cox M Binsfeld C Hao Z Brustle A Itsumi M Glutathione primes T cell metabolism for inflammation Immunity 2017 46 675 689 28423341
  35. [37]Suthanthiran M Anderson ME Sharma VK Meister A Glutathione regulates activation-dependent DNA synthesis in highly purified normal human T lymphocytes stimulated via the CD2 and CD3 antigens Proc Natl Acad Sci USA 1990 87 3343 3347 1970635 PMC53896
  36. [38]Hadzic T Li L Cheng N Walsh SA Spitz DR Knudson CM The role of low molecular weight thiols in T lymphocyte proliferation and IL-2 secretion J Immunol 2005 175 7965 7972 16339532
  37. [39]Friesen C Kiess Y Debatin KM A critical role of glutathione in determining apoptosis sensitivity and resistance in leukemia cells Cell Death Differ 2004 11 Suppl 1 S73 S85 15105835
  38. [40]Franco R Cidlowski JA SLCO/OATP-like transport of glutathione in FasL-induced apoptosis: glutathione efflux is coupled to an organic anion exchange and is necessary for the progression of the execution phase of apoptosis J Biol Chem 2006 281 29542 29557 16857677
  39. [41]Ghibelli L Fanelli C Rotilio G Lafavia E Coppola S Colussi C Civitareale P Ciriolo MR Rescue of cells from apoptosis by inhibition of active GSH extrusion FASEB J 1998 12 479 486 9535220
  40. [45]Cullinan SB Gordan JD Jin J Harper JW Diehl JA The Keap1-BTB protein is an adaptor that bridges Nrf2 to a Cul3-based E3 ligase: oxidative stress sensing by a Cul3-Keap1 ligase Mol Cell Biol 2004 24 8477 8486 15367669 PMC516753
  41. [46]Jaramillo MC Zhang DD The emerging role of the Nrf2-Keap1 signaling pathway in cancer Genes Dev 2013 27 2179 2191 24142871 PMC3814639
  42. [49]Furukawa M Xiong Y BTB protein Keap1 targets antioxidant transcription factor Nrf2 for ubiquitination by the Cullin 3-Roc1 ligase Mol Cell Biol 2005 25 162 171 15601839 PMC538799
  43. [50]Turley AE Zagorski JW Rockwell CE The Nrf2 activator tBHQ inhibits T cell activation of primary human CD4 T cells Cytokine 2015 71 289 295 25484350 PMC4297602
  44. [51]Zagorski JW Turley AE Dover HE VanDenBerg KR Compton JR Rockwell CE The Nrf2 activator, tBHQ, differentially affects early events following stimulation of Jurkat cells Toxicol Sci 2013 136 63 71 23945499 PMC3829568
  45. [52]Suzuki T Murakami S Biswal SS Sakaguchi S Harigae H Yamamoto M Motohashi H Systemic activation of NRF2 alleviates lethal autoimmune inflammation in scurfy mice Mol Cell Biol 2017 37 e00063 e17 28507037 PMC5514445
  46. [53]Rockwell CE Zhang M Fields PE Klaassen CD Th2 skewing by activation of Nrf2 in CD4(+) T cells J Immunol 2012 188 1630 1637 22250088 PMC3273574
  47. [54]Zhao M Chen H Ding Q Xu X Yu B Huang Z Nuclear factor erythroid 2-related factor 2 deficiency exacerbates lupus nephritis in B6/lpr mice by regulating Th17 cell function Sci Rep 2016 6 38619 27941837 PMC5150244
  48. [55]Noel S Martina MN Bandapalle S Racusen LC Potteti HR Hamad AR Reddy SP Rabb H T lymphocyte-specific activation of Nrf2 protects from AKI J Am Soc Nephrol 2015 26 2989 3000 26293820 PMC4657838
  49. [56]Kesarwani P Thyagarajan K Chatterjee S Palanisamy V Mehrotra S Anti-oxidant capacity and anti-tumor T cell function: a direct correlation OncoImmunology 2015 4 e985942 25949871 PMC4368125
  50. [57]Scheffel MJ Scurti G Simms P Garrett-Mayer E Mehrotra S Nishimura MI Voelkel-Johnson C Efficacy of adoptive T-cell therapy is improved by treatment with the antioxidant N-acetyl cysteine, which limits activation-induced T-cell death Cancer Res 2016 76 6006 6016 27742673 PMC5074089
  51. [59]Chen HY Chen RH Cullin 3 ubiquitin ligases in cancer biology: functions and therapeutic implications Front Oncol 2016 6 113 27200299 PMC4852199
  52. [60]Rushworth SA Macewan DJ The role of nrf2 and cytoprotection in regulating chemotherapy resistance of human leukemia cells Cancers (Basel) 2011 3 1605 1621 24212776 PMC3757381
  53. [61]Konstantinopoulos PA Spentzos D Fountzilas E Francoeur N Sanisetty S Grammatikos AP Hecht JL Cannistra SA Keap1 mutations and Nrf2 pathway activation in epithelial ovarian cancer Cancer Res 2011 71 5081 5089 21676886
  54. [62]Ohta T Iijima K Miyamoto M Nakahara I Tanaka H Ohtsuji M Suzuki T Kobayashi A Yokota J Sakiyama T Loss of Keap1 function activates Nrf2 and provides advantages for lung cancer cell growth Cancer Res 2008 68 1303 1309 18316592
  55. [63]Yoo NJ Kim HR Kim YR An CH Lee SH Somatic mutations of the KEAP1 gene in common solid cancers Histopathology 2012 60 943 952 22348534
  56. [64]Broccoli A Argnani L Zinzani PL Peripheral T-cell lymphomas: Focusing on novel agents in relapsed and refractory disease Cancer Treat Rev 2017 60 120 129 28946015
  57. [65]Rewa O Bagshaw SM Acute kidney injury-epidemiology, outcomes and economics Nat Rev Nephrol 2014 10 193 207 24445744
  58. [66]Rabb H Daniels F O'Donnell M Haq M Saba SR Keane W Tang WW Pathophysiological role of T lymphocytes in renal ischemia-reperfusion injury in mice Am J Physiol Renal Physiol 2000 279 F525 F531 10966932
  59. [67]Johnson DA Amirahmadi S Ward C Fabry Z Johnson JA The absence of the pro-antioxidant transcription factor Nrf2 exacerbates experimental autoimmune encephalomyelitis Toxicol Sci 2010 114 237 246 19910389 PMC2902921
  60. [68]Kuo PC Brown DA Scofield BA Yu IC Chang FL Wang PY Yen JH 3H-1,2-dithiole-3-thione as a novel therapeutic agent for the treatment of experimental autoimmune encephalomyelitis Brain Behav Immun 2016 57 173 186 27013356
  61. [69]Kozela E Juknat A Gao F Kaushansky N Coppola G Vogel Z Pathways and gene networks mediating the regulatory effects of cannabidiol, a nonpsychoactive cannabinoid, in autoimmune T cells J Neuroinflammation 2016 13 136 27256343 PMC4891926
  62. [70]Pareek TK Belkadi A Kesavapany S Zaremba A Loh SL Bai L Cohen ML Meyer C Liby KT Miller RH Triterpenoid modulation of IL-17 and Nrf-2 expression ameliorates neuroinflammation and promotes remyelination in autoimmune encephalomyelitis Sci Rep 2011 1 201 22355716 PMC3242013
  63. [71]Larabee CM Desai S Agasing A Georgescu C Wren JD Axtell RC Plafker SM Loss of Nrf2 exacerbates the visual deficits and optic neuritis elicited by experimental autoimmune encephalomyelitis Mol Vis 2016 22 1503 1513 28050123 PMC5204460
  64. [72]Breuer J Herich S Schneider-Hohendorf T Chasan AI Wettschureck N Gross CC Loser K Zarbock A Roth J Klotz L Dual action by fumaric acid esters synergistically reduces adhesion to human endothelium Mult Scler 10.1177/1352458517735189 28984166 · DOI

Cited by

Sorted by citations

Authors
Yarosz, E. L., & Chang, C.-H.
Affiliations
University of Michigan (US)
Corresponding author
Chang, Cheong-Hee
Venue
Immune Network
Publisher
XMLink
Published
2018
Volume
18
Issue
1
Pages
e14-e14
ISSN
  • 1598-2629 (ISSN-L)
  • 2092-6685
OpenAlex
W2791277314
Cited by
214
References
8
Citations by year
2026: 21 · 2025: 19 · 2024: 39 · 2023: 24 · 2022: 30 · 2021: 32 · 2020: 33 · 2019: 13 · 2018: 2 · 2017: 1
FWCI
1.96
Type
journal article
Language
en
Open access
Locations
  • Immune Network (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
Funders
National Institutes of Health (AI121156, T32 AI007413)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
  • Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
Keywords
reactive oxygen species, T cell immunity, T cell activation, T cell receptor signaling, second messengers, T cell metabolism, glutathione pathway, antioxidant pathways, oxidative stress, autoimmune disease, T cell subsets

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review