Manipulating the bioenergetics of alloreactive T cells causes their selective apoptosis and arrests graft-versus-host disease
Open accessAbstract
Cells generate adenosine triphosphate (ATP) by glycolysis and by oxidative phosphorylation (OXPHOS). Despite the importance of having sufficient ATP available for the energy-dependent processes involved in immune activation, little is known about the metabolic adaptations that occur in vivo to meet the increased demand for ATP in activated and proliferating lymphocytes. We found that bone marrow (BM) cells proliferating after BM transplantation (BMT) increased aerobic glycolysis but not OXPHOS, whereas T cells proliferating in response to alloantigens during graft-versus-host disease (GVHD) increased both aerobic glycolysis and OXPHOS. Metabolomic analysis of alloreactive T cells showed an accumulation of acylcarnitines consistent with changes in fatty acid oxidation. Alloreactive T cells also exhibited a hyperpolarized mitochondrial membrane potential (ΔΨm), increased superoxide production, and decreased amounts of antioxidants, whereas proliferating BM cells did not. Bz-423, a small-molecule inhibitor of the mitochondrial F(1)F(0) adenosine triphosphate synthase (F(1)F(0)-ATPase), selectively increased superoxide and induced the apoptosis of alloreactive T cells, which arrested established GVHD in several BMT models without affecting hematopoietic engraftment or lymphocyte reconstitution. These findings challenge the current paradigm that activated T cells meet their increased demands for ATP through aerobic glycolysis, and identify the possibility that bioenergetic and redox characteristics can be selectively exploited as a therapeutic strategy for immune disorders.
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In multiple bone marrow transplant models, Bz-423, which inhibits mitochondrial ATP synthase, stopped established graft-versus-host disease while leaving hematopoietic engraftment and lymphocyte reconstitution intact.
“Moreover, Bz-423, a small-molecule inhibitor of the mitochondrial ATP-synthase, arrested established graft versus host disease (GVHD) in several bone marrow transplant models without affecting hematopoietic engraftment or lymphocyte reconstitution (Gatza et al., 2011).”
From Mitochondria in the Regulation of Innate and Adaptive Immunity (2015) · cites this paper as Gatza et al., 2011
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Cites
Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation
Vander Heiden, M. G., Cantley, L. C., & Thompson, C. B. (2009) · Science · doi:10.1126/science.1160809 · Cited by 16,197 · see citing works
Ferrara, J. L. M., Levine, J. E., Reddy, P. R., & Holler, E. (2009) · The Lancet · doi:10.1016/s0140-6736(09)60237-3 · Cited by 2,508 · see citing works
Self-citationKorshunov, S. S., Skulachev, V. P., & Starkov, A. A. (1997) · FEBS Letters · doi:10.1016/s0014-5793(97)01159-9 · Cited by 1,727 · see citing works
mTOR regulates memory CD8 T-cell differentiation
Araki, K., Turner, A. P., Shaffer, V. O., Gangappa, S., Keller, S. A., Bachmann, M. F., Larsen, C. P., & Ahmed, R. (2009) · Nature · doi:10.1038/nature08155 · Cited by 1,575 · see citing works
Enhancing CD8 T-cell memory by modulating fatty acid metabolism
Pearce, E. L., Walsh, M. C., Cejas, P. J., Harms, G. M., Shen, H., Wang, L.-S., Jones, R. G., & Choi, Y. (2009) · Nature · doi:10.1038/nature08097 · Cited by 1,559 · see citing works
Prevention of Graft Versus Host Disease by Inactivation of Host Antigen-Presenting Cells
Shlomchik, W. D., Couzens, M. S., Tang, C. B., McNiff, J. M., Robert, M. E., Liu, J., Shlomchik, M. J., & Emerson, S. G. (1999) · Science · doi:10.1126/science.285.5426.412 · Cited by 1,181 · see citing works
Simsek, T., Kocabas, F., Zheng, J., DeBerardinis, R. J., Mahmoud, A. I., Olson, E. N., Schneider, J. W., Zhang, C. C., & Sadek, H. A. (2010) · Cell Stem Cell · doi:10.1016/j.stem.2010.07.011 · Cited by 1,101 · see citing works
Fuel feeds function: energy metabolism and the T-cell response
Fox, C. J., Hammerman, P. S., & Thompson, C. B. (2005) · Nature reviews. Immunology · doi:10.1038/nri1710 · Cited by 854 · see citing works
Hill, G. R., Crawford, J. M., Cooke, K. R., Brinson, Y. S., Pan, L., & Ferrara, J. L. M. (1997) · Blood · doi:10.1182/blood.v90.8.3204 · Cited by 833 · see citing works
Self-citationGlucocorticoids in T Cell Development and Function
Ashwell, J. D., Lu, F. W. M., & Vacchio, M. S. (2000) · Annual Review of Immunology · doi:10.1146/annurev.immunol.18.1.309 · Cited by 777 · see citing works
Schieke, S. M., Phillips, D., McCoy, J. P., Aponte, A. M., Shen, R.-F., Balaban, R. S., & Finkel, T. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m603536200 · Cited by 623 · see citing works
Almost all about citrulline in mammals
Curis, E., Nicolis, I., Moinard, C., Osowska, S., Zerrouk, N., Bénazeth, S., & Cynober, L. (2005) · Amino Acids · doi:10.1007/s00726-005-0235-4 · Cited by 571 · see citing works
Mitochondrial membrane potential and neuronal glutamate excitotoxicity: mortality and millivolts
Nicholls, D. G., & Ward, M. W. (2000) · Trends in Neurosciences · doi:10.1016/s0166-2236(99)01534-9 · Cited by 563 · see citing works
Dai, J., Weinberg, R. S., Waxman, S., & Jing, Y. (1999) · Blood · doi:10.1182/blood.v93.1.268 · Cited by 540 · see citing works
MacIver, N. J., Jacobs, S. R., Wieman, H. L., Wofford, J. A., Coloff, J. L., & Rathmell, J. C. (2008) · Journal of Leukocyte Biology · doi:10.1189/jlb.0108024 · Cited by 501 · see citing works
Critical evaluation of the use of hydroethidine as a measure of superoxide anion radical
Benov, L., Sztejnberg, L., & Fridovich, I. (1998) · Free Radical Biology and Medicine · doi:10.1016/s0891-5849(98)00163-4 · Cited by 495 · see citing works
Q-VD-OPh, a broad spectrum caspase inhibitor with potent antiapoptotic properties
Caserta, T. M., Smith, A. N., Gultice, A. D., Reedy, M., & Brown, T. L. (2003) · APOPTOSIS · doi:10.1023/a:1024116916932 · Cited by 408 · see citing works
Vaughn, A. E., & Deshmukh, M. (2008) · Nature Cell Biology · doi:10.1038/ncb1807 · Cited by 408 · see citing works
The efficiency and plasticity of mitochondrial energy transduction.
Brand, M. D. (2005) · Biochemical Society Transactions · doi:10.1042/bst0330897 · Cited by 406 · see citing works
Brand, K. A., & Hermfisse, U. (1997) · The FASEB Journal · doi:10.1096/fasebj.11.5.9141507 · Cited by 401 · see citing works
Beilhack, A., Schulz, S., Baker, J. B., Beilhack, G. F., Wieland, C. B., Herman, E. I., Baker, E. M., Cao, Y., Contag, C. H., & Negrin, R. S. (2005) · Blood · doi:10.1182/blood-2005-02-0509 · Cited by 352 · see citing works
Revving the Engine: Signal Transduction Fuels T Cell Activation
Jones, R. G., & Thompson, C. B. (2007) · Immunity · doi:10.1016/j.immuni.2007.07.008 · Cited by 349 · see citing works
Effects of Cyclosporine A on T Cell Development and Clonal Deletion
Jenkins, M. K., Schwartz, R. H., & Pardoll, D. M. (1988) · Science · doi:10.1126/science.3262237 · Cited by 343 · see citing works
Greiner, E. F., Guppy, M., & Brand, K. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)31720-4 · Cited by 307 · see citing works
Resistance to Paclitaxel Is Proportional to Cellular Total Antioxidant Capacity
Ramanathan, B., Jan, K.-Y., Chen, C., Hour, T., Yu, H., & Pu, Y. (2005) · Cancer Research · doi:10.1158/0008-5472.can-05-1162 · Cited by 287 · see citing works
Hill, B. G., Dranka, B. P., Zou, L., Chatham, J. C., & Darley-Usmar, V. M. (2009) · Biochemical Journal · doi:10.1042/bj20090934 · Cited by 284 · see citing works
Gatza, E., Rogers, C. E., Clouthier, S. G., et al. (2008) · Blood · doi:10.1182/blood-2007-11-125542 · Cited by 215 · see citing works
Self-citationJohnson, K. M., Chen, X., Boitano, A. E., Swenson, L., Opipari, A. W., & Glick, G. D. (2005) · Chemistry & Biology · doi:10.1016/j.chembiol.2005.02.012 · Cited by 127 · see citing works
Self-citationCharacterization of the metabolic phenotype of chronically activated lymphocytes
Wahl, D., Petersen, B., Warner, R. E., Richardson, B. C., Glick, G. D., & Opipari, A. (2010) · Lupus · doi:10.1177/0961203310373109 · Cited by 82 · see citing works
Self-citationAcute graft-versus-host disease: new treatment strategies
Paczesny, S., Choi, S. W., & Ferrara, J. L. M. (2009) · Current Opinion in Hematology · doi:10.1097/moh.0b013e3283319a6f · Cited by 73 · see citing works
Self-citationHarris, S. I., Balaban, R. S., & Mandel, L. J. (1980) · Science · doi:10.1126/science.6246581 · Cited by 64 · see citing works
Nitric oxide, mitochondrial hyperpolarization, and T cell activation
Nagy, G., Koncz, Á., Fernández, D., & Perl, A. (2007) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2007.02.026 · Cited by 63 · see citing works
Blatt, N. B., Bednarski, J. J., Warner, R. E., et al. (2002) · Journal of Clinical Investigation · doi:10.1172/jci16029 · Cited by 63 · see citing works
Blatt, N. B., Bednarski, J. J., Warner, R. E., et al. (2002) · Journal of Clinical Investigation · doi:10.1172/jci0216029 · Cited by 59 · see citing works
Differential Requirement for IFN-γ in CTL Maturation in Acute Murine Graft-versus-Host Disease
Puliaev, R., Nguyen, P., Finkelman, F. D., et al. (2004) · The Journal of Immunology · doi:10.4049/jimmunol.173.2.910 · Cited by 54 · see citing works
Attenuation of autoimmune disease in fas‐deficient mice by treatment with a cytotoxic benzodiazepine
Bednarski, J. J., Warner, R. E., Rao, T., et al. (2003) · Arthritis & Rheumatism · doi:10.1002/art.10968 · Cited by 49 · see citing works
Chapter Twenty‐Two Mechanisms and Methods in Glucose Metabolism and Cell Death
Zhao, Y., Wieman, H. L., Jacobs, S. R., et al. (2008) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/s0076-6879(08)01422-5 · Cited by 45 · see citing works
Kuhnke, A., Burmester, G. R., Krauss, S., & Buttgereit, F. (2003) · Annals of the Rheumatic Diseases · doi:10.1136/ard.62.2.133 · Cited by 44 · see citing works
Cavazzana, M., André‐Schmutz, I., Cortivo, L. D., Neven, B., Hacein‐Bey‐Abina, S., & Fischer, A. (2009) · Current Opinion in Immunology · doi:10.1016/j.coi.2009.08.001 · Cited by 41 · see citing works
Morales, M.-C., Pérez‐Yarza, G., Nieto-Rementería, N., et al. (2005) · PubMed · Cited by 38 · see citing works
Comparison of energy metabolism in human normal and neoplastic (Burkitt's lymphoma) lymphoid cells.
Sariban-Sohraby, S., MAGRATH, I. T., & Balaban, R. S. (1983) · PubMed · Cited by 34 · see citing works
Effects of cyclosporine A on T cell development and clonal deletion
Jenkins, M. K., Schwartz, R. H., & Pardoll, D. (1988) · Science · doi:10.1126/science.241.4873.1655 · Cited by 31 · see citing works
Bz-423 superoxide signals apoptosis via selective activation of JNK, Bak, and Bax
Blatt, N. B., Boitano, A. E., Lyssiotis, C. A., Opipari, A. W., & Glick, G. D. (2008) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2008.07.022 · Cited by 29 · see citing works
Self-citationManifestations and Treatment of Acute Graft‐versus‐Host Disease
Cutler, C. S., & Antin, J. H. (2015) · doi:10.1002/9781118416426.ch83 · Cited by 25 · see citing works
Manifestations and Treatment of Acute Graft‐Versus‐Host Disease
Cutler, C. S., & Antin, J. H. (2009) · doi:10.1002/9781444303537.ch86 · Cited by 12 · see citing works
Sundberg, T. B., Swenson, L., Wahl, D. R., et al. (2009) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.109.156422 · Cited by 11 · see citing works
Self-citation(2017) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2017.08.172 · Cited by 5 · see citing works
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- [3]Voet D Voet JG Biochemistry 3 2004 New York J. Wiley & Sons xv 1591
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Posttranscriptional Control of T Cell Effector Function by Aerobic Glycolysis
Chang, C.-H., Curtis, J. D., Maggi, L. B., Faubert, B., Villarino, A. V., O’Sullivan, D., Huang, S. C.-C., van der Windt, G. J. W., Blagih, J., Qiu, J., et al. (2013) · Cell · doi:10.1016/j.cell.2013.05.016 · Cited by 2,204 · see citing works
Metabolic Regulation of T Lymphocytes
MacIver, N. J., Michalek, R. D., & Rathmell, J. C. (2013) · Annual Review of Immunology · doi:10.1146/annurev-immunol-032712-095956 · Cited by 1,244 · see citing works
Mitochondria in the Regulation of Innate and Adaptive Immunity
Weinberg, S. E., Sena, L. A., & Chandel, N. S. (2015) · Immunity · doi:10.1016/j.immuni.2015.02.002 · Cited by 960 · see citing works
Metabolism of immune cells in cancer
Leone, R. D., & Powell, J. D. (2020) · Nature Reviews Cancer · doi:10.1038/s41568-020-0273-y · Cited by 877 · see citing works
Metabolic switching and fuel choice during T‐cell differentiation and memory development
van der Windt, G. J. W., & Pearce, E. L. (2012) · Immunological Reviews · doi:10.1111/j.1600-065x.2012.01150.x · Cited by 563 · see citing works
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Waickman, A. T., & Powell, J. D. (2012) · Immunological Reviews · doi:10.1111/j.1600-065x.2012.01152.x · Cited by 420 · see citing works
Energy metabolism and rheumatic diseases: from cell to organism
Spies, C. M., Straub, R. H., & Buttgereit, F. (2012) · Arthritis Research & Therapy · doi:10.1186/ar3885 · Cited by 47 · see citing works
- Authors
- Gatza, E., Wahl, D. R., Opipari, A. W., Sundberg, T. B., Reddy, P., Liu, C., Glick, G. D., & Ferrara, J. L. M.
- Affiliations
- University of Michigan (US)
- University of Florida Health (US)
- Corresponding author
- Gatza, Erin
- Wahl, Daniel R.
- Sundberg, Thomas B.
- Glick, Gary D.
- Ferrara, James L. M.
- ORCID
- Venue
- Science Translational Medicine
- Published
- 2011-01-26
- Volume
- 3
- Issue
- 67
- Pages
- 67ra8-67ra8
- ISSN
- 1946-6234 (ISSN-L)
- 1946-6242
- PMC
- PMC3364290
- OpenAlex
- W2168632418
- Cited by
- 168
- References
- 47
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 5 · 2023: 8 · 2022: 6 · 2021: 15 · 2020: 18 · 2019: 14 · 2018: 10 · 2017: 14 · 2016: 19 · 2015: 14 · 2014: 14 · 2013: 11 · 2012: 12
- FWCI
- 4.25
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science Translational Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Heart, Lung, and Blood Institute (T32HL007622)
- National Cancer Institute (P01-CA-39542, T32 CA88784-04, T32CA088784, P01CA039542, T32CA009676)
- National Institute of Allergy and Infectious Diseases (AI 047450, R21AI047450, R01AI047450)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- alloreactive T cells, graft-versus-host disease, aerobic glycolysis, oxidative phosphorylation, mitochondrial membrane potential, superoxide, fatty acid oxidation, acylcarnitines, T cell apoptosis, bone marrow transplantation, T cell metabolism, redox signaling
- MeSH terms
- Animals, Benzodiazepines, Bone Marrow Cells, Female, Graft vs Host Disease, Isoantigens, Lactates, Lymphocyte Activation, Mice, Inbred BALB C, Mice, Inbred C57BL, Oxidative Phosphorylation, Oxygen Consumption, T-Lymphocytes, Bone Marrow Transplantation, Apoptosis, Reactive Oxygen Species, Mitochondrial Proton-Translocating ATPases, Mice, Metabolome
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