PDF
ePub
Citation
Print
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.
References
1. Ray PD, Huang BW, Tsuji Y. Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signaling. Cell Signal. 2012; 24:981–990.
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.
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.
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.
5. Weinberg F, Hamanaka R, Wheaton WW, Weinberg S, Joseph J, Lopez M, Kalyanaraman B, Mutlu GM, Budinger GR, Chandel NS. Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity. Proc Natl Acad Sci U S A. 2010; 107:8788–8793.
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.
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.
8. Loschen G, Azzi A, Flohe L. Mitochondrial H2O2 formation: relationship with energy conservation. FEBS Lett. 1973; 33:84–87.
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.
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.
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.
12. Turrens JF, Boveris A. Generation of superoxide anion by the NADH dehydrogenase of bovine heart mitochondria. Biochem J. 1980; 191:421–427.
13. Lenaz G. The mitochondrial production of reactive oxygen species: mechanisms and implications in human pathology. IUBMB Life. 2001; 52:159–164.
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.
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.
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.
17. Pearce EL, Poffenberger MC, Chang CH, Jones RG. Fueling immunity: insights into metabolism and lymphocyte function. Science. 2013; 342:1242454.
18. Kamiński MM, Sauer SW, Kamiński M, Opp S, Ruppert T, Grigaravič ius 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 Rep. 2012; 2:1300–1315.
19. Sena LA, Li S, Jairaman A, Prakriya M, Ezponda T, Hildeman DA, Wang CR, Schumacker PT, Licht JD, Perlman H, et al. Mitochondria are required for antigen-specific T cell activation through reactive oxygen species signaling. Immunity. 2013; 38:225–236.
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.
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.
22. Devadas S, Zaritskaya L, Rhee SG, Oberley L, Williams MS. 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; 195:59–70.
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.
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.
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.
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.
27. Fu G, Xu Q, Qiu Y, Jin X, Xu T, Dong S, Wang J, Ke Y, Hu H, Cao X, et al. Suppression of Th17 cell differentiation by misshapen/NIK-related kinase MINK1. J Exp Med. 2017; 214:1453–1469.
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.
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.
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 U S A. 1993; 90:4409–4413.
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.
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.
33. Bennett SJ, Griffiths HR. Regulation of T-cell functions by oxidative stress. Studies on Arthritis and Joint Disorders. Alcaraz MJ, Gualillo O, Sánchez-Pernaute O, editors. eds.New York, NY: Humana Press;2013. p. 33–48.
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.
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.
36. Mak TW, Grusdat M, Duncan GS, Dostert C, Nonnenmacher Y, Cox M, Binsfeld C, Hao Z, Brustle A, Itsumi M, et al. Glutathione primes T cell metabolism for inflammation. Immunity. 2017; 46:675–689.
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 U S A. 1990; 87:3343–3347.
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.
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.
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.
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.
42. Itoh K, Chiba T, Takahashi S, Ishii T, Igarashi K, Katoh Y, Oyake T, Hayashi N, Satoh K, Hatayama I, et al. An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements. Biochem Biophys Res Commun. 1997; 236:313–322.
43. Liu Y, Kern JT, Walker JR, Johnson JA, Schultz PG, Luesch H. A genomic screen for activators of the antioxidant response element. Proc Natl Acad Sci U S A. 2007; 104:5205–5210.
44. Moi P, Chan K, Asunis I, Cao A, Kan YW. Isolation of NF-E2-related factor 2 (Nrf2), a NF-E2-like basic leucine zipper transcriptional activator that binds to the tandem NF-E2/AP1 repeat of the beta-globin locus control region. Proc Natl Acad Sci U S A. 1994; 91:9926–9930.
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.
46. Jaramillo MC, Zhang DD. The emerging role of the Nrf2-Keap1 signaling pathway in cancer. Genes Dev. 2013; 27:2179–2191.
47. Itoh K, Wakabayashi N, Katoh Y, Ishii T, Igarashi K, Engel JD, Yamamoto M. Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Genes Dev. 1999; 13:76–86.
48. Kobayashi A, Kang MI, Okawa H, Ohtsuji M, Zenke Y, Chiba T, Igarashi K, Yamamoto M. Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate proteasomal degradation of Nrf2. Mol Cell Biol. 2004; 24:7130–7139.
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.
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.
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.
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:e00063–17.
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.
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.
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.
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.
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.
58. Mitsuishi Y, Taguchi K, Kawatani Y, Shibata T, Nukiwa T, Aburatani H, Yamamoto M, Motohashi H. Nrf2 redirects glucose and glutamine into anabolic pathways in metabolic reprogramming. Cancer Cell. 2012; 22:66–79.
59. Chen HY, Chen RH. Cullin 3 ubiquitin ligases in cancer biology: functions and therapeutic implications. Front Oncol. 2016; 6:113.
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.
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.
62. Ohta T, Iijima K, Miyamoto M, Nakahara I, Tanaka H, Ohtsuji M, Suzuki T, Kobayashi A, Yokota J, Sakiyama T, et al. Loss of Keap1 function activates Nrf2 and provides advantages for lung cancer cell growth. Cancer Res. 2008; 68:1303–1309.
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.
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.
65. Rewa O, Bagshaw SM. Acute kidney injury-epidemiology, outcomes and economics. Nat Rev Nephrol. 2014; 10:193–207.
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.
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.
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.
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.
70. Pareek TK, Belkadi A, Kesavapany S, Zaremba A, Loh SL, Bai L, Cohen ML, Meyer C, Liby KT, Miller RH, et al. Triterpenoid modulation of IL-17 and Nrf-2 expression ameliorates neuroinflammation and promotes remyelination in autoimmune encephalomyelitis. Sci Rep. 2011; 1:201.
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.
72. Breuer J, Herich S, Schneider-Hohendorf T, Chasan AI, Wettschureck N, Gross CC, Loser K, Zarbock A, Roth J, Klotz L, et al. Dual action by fumaric acid esters synergistically reduces adhesion to human endothelium. Mult Scler.DOI: doi: 10.1177/1352458517735189.
Figure 1.
ROS modulate several aspects of T cell-mediated immunity downstream of TCR stimulation. (A) Following activation, signaling through the TCR stimulates the mitochondria to produce ROS, which in turn promote continued TCR signaling. The level of activation-induced ROS within the cell also critically affects the downstream functions of T cell proliferation, differentiation, and survival. Therefore, the modulation of ROS levels by cellular antioxidant pathways (e.g., GSH; Nrf2-Keap1-Cul3 trimeric complex) is crucial in maintaining proper T cell-mediated immunity. GSH regulates ROS levels by directly reducing free radicals encountered in the cytoplasm. In contrast, the Nrf2-Keap1-Cul3 trimeric complex disassociates upon sensing high levels of cellular ROS, allowing Nrf2 to enter the nucleus and activate the ARE-containing genes. (B) If cellular antioxidant pathways are dysregulated or mutated, cellular ROS levels will not be properly controlled. Therefore, high levels of ROS after T cell activation can lead to the development of several T cell-mediated autoimmune diseases and cancer. APC, antigen presenting cell; MHC, major histocompatibility complex.
XML Download