Targeting age-specific changes in CD4 T cell metabolism ameliorates alloimmune responses and prolongs graft survival.
Authors:
Journal: Aging cell
Publication Type: Journal Article
Date: 2021
DOI: PMC7884034
ID: 33497523
Abstract
Age impacts alloimmunity. Effects of aging on T-cell metabolism and the potential to interfere with immunosuppressants have not been explored yet. Here, we dissected metabolic pathways of CD4 and CD8 T cells in aging and offer novel immunosuppressive targets. Upon activation, CD4 T cells from old mice failed to exhibit adequate metabolic reprogramming resulting into compromised metabolic pathways, including oxidative phosphorylation (OXPHOS) and glycolysis. Comparable results were also observed in elderly human patients. Although glutaminolysis remained the dominant and age-independent source of mitochondria for activated CD4 T cells, old but not young CD4 T cells relied heavily on glutaminolysis. Treating young and old murine and human CD4 T cells with 6-diazo-5-oxo-l-norleucine (DON), a glutaminolysis inhibitor resulted in significantly reduced IFN-γ production and compromised proliferative capacities specifically of old CD4 T cells. Of translational relevance, old and young mice that had been transplanted with fully mismatched skin grafts and treated with DON demonstrated dampened Th1- and Th17-driven alloimmune responses. Moreover, DON diminished cytokine production and proliferation of old CD4 T cells in vivo leading to a significantly prolonged allograft survival specifically in old recipients. Graft prolongation in young animals, in contrast, was only achieved when DON was applied in combination with an inhibition of glycolysis (2-deoxy-d-glucose, 2-DG) and OXPHOS (metformin), two alternative metabolic pathways. Notably, metabolic treatment had not been linked to toxicities. Remarkably, immunosuppressive capacities of DON were specific to CD4 T cells as adoptively transferred young CD4 T cells prevented immunosuppressive capacities of DON on allograft survival in old recipients. Depletion of CD8 T cells did not alter transplant outcomes in either young or old recipients. Taken together, our data introduce an age-specific metabolic reprogramming of CD4 T cells. Targeting those pathways offers novel and age-specific approaches for immunosuppression.
Reference List
- Alegre, M. L. , Lakkis, F. G. , & Morelli, A. E. (2016). Antigen presentation in transplantation. Trends in Immunology, 37(12), 831–843. 10.1016/j.it.2016.09.003.|||Barnden, M. J. , Allison, J. , Heath, W. R. , & Carbone, F. R. (1998). Defective TCR expression in transgenic mice constructed using cDNA‐based alpha‐ and beta‐chain genes under the control of heterologous regulatory elements. Immunology and Cell Biology, 76(1), 34–40. 10.1046/j.1440-1711.1998.00709.x|||Bedi, D. S. , Krenzien, F. , Quante, M. , Uehara, H. , Edtinger, K. , Liu, G. , Denecke, C. , Jurisch, A. , Kim, I. , Li, H. , Yuan, X. , Ge, X. , ElKhal, A. , & Tullius, S. G. (2016). Defective CD8 signaling pathways delay rejection in older recipients. Transplantation, 100(1), 69–79. 10.1097/tp.0000000000000886|||Bektas, A. , Schurman, S. H. , Sen, R. , & Ferrucci, L. (2017). Human T cell immunosenescence and inflammation in aging. Journal of Leukocyte Biology, 102(4), 977–988. 10.1189/jlb.3RI0716-335R|||Buchholz, M. , Schatz, A. , Wagner, M. , Michl, P. , Linhart, T. , Adler, G. , Gress, T. M. , & Ellenrieder, V. (2006). Overexpression of c‐myc in pancreatic cancer caused by ectopic activation of NFATc1 and the Ca2+/calcineurin signaling pathway. EMBO Journal, 25(15), 3714–3724. 10.1038/sj.emboj.7601246|||Busse, D. , de la Rosa, M. , Hobiger, K. , Thurley, K. , Flossdorf, M. , Scheffold, A. , & Höfer, T. (2010). Competing feedback loops shape IL‐2 signaling between helper and regulatory T lymphocytes in cellular microenvironments. Proceedings of the National Academy of Sciences of the United States of America, 107(7), 3058–3063. 10.1073/pnas.0812851107.|||Chambers, J. W. , Maguire, T. G. , & Alwine, J. C. (2010). Glutamine metabolism is essential for human cytomegalovirus infection. Journal of Virology, 84(4), 1867–1873. 10.1128/jvi.02123-09|||Chung, Y. W. , Chung, M. W. , Choi, S. K. , Choi, S. J. , Choi, S. J. N. , & Chung, S. Y. (2018). Tacrolimus‐induced apoptosis is mediated by endoplasmic reticulum‐derived calcium‐dependent caspases‐3,‐12 in Jurkat cells. Transplantation Proceedings, 50(4), 1172–1177. 10.1016/j.transproceed.2018.01.050.|||Colvin, M. M. , Smith, C. A. , Tullius, S. G. , & Goldstein, D. R. (2017). Aging and the immune response to organ transplantation. Journal of Clinical Investigation, 127(7), 2523–2529. 10.1172/jci90601|||Cortassa, S. , Aon, M. A. , & Sollott, S. J. (2019). Control and regulation of substrate selection in cytoplasmic and mitochondrial catabolic networks. A systems biology analysis. Frontiers in Physiology, 10, 201 10.3389/fphys.2019.00201|||De Serres, S. A. , Sayegh, M. H. , & Najafian, N. (2009). Immunosuppressive drugs and Tregs: A critical evaluation!. Clinical Journal of the American Society of Nephrology, 4(10), 1661 10.2215/CJN.03180509|||DeWolf, S. , & Sykes, M. (2017). Alloimmune T cells in transplantation. Journal of Clinical Investigation, 127(7), 2473–2481. 10.1172/jci90595|||Duran, R. V. , Oppliger, W. , Robitaille, A. M. , Heiserich, L. , Skendaj, R. , Gottlieb, E. , & Hall, M. N. (2012). Glutaminolysis activates Rag‐mTORC1 signaling. Molecular Cell, 47(3), 349–358. 10.1016/j.molcel.2012.05.043|||Fernandez‐Ramos, A. A. , Poindessous, V. , Marchetti‐Laurent, C. , Pallet, N. , & Loriot, M. A. (2016). The effect of immunosuppressive molecules on T‐cell metabolic reprogramming. Biochimie, 127, 23–36. 10.1016/j.biochi.2016.04.016|||Fracchia, K. M. , Pai, C. Y. , & Walsh, C. M. (2013). Modulation of T cell metabolism and function through calcium signaling. Frontiers in Immunology, 4, 324 10.3389/fimmu.2013.00324|||Ganeshan, K. , & Chawla, A. (2014). Metabolic regulation of immune responses. Annual Review of Immunology, 32, 609–634. 10.1146/annurev-immunol-032713-120236|||Gómez, L. A. , & Hagen, T. M. (2012). Age‐related decline in mitochondrial bioenergetics: does supercomplex destabilization determine lower oxidative capacity and higher superoxide production? Seminars in Cell & Developmental Biology, 23(7), 758–767. 10.1016/j.semcdb.2012.04.002|||Gross, M. I. , Demo, S. D. , Dennison, J. B. , Chen, L. , Chernov‐Rogan, T. , Goyal, B. , Janes, J. R. , Laidig, G. J. , Lewis, E. R. , Li, J. , MacKinnon, A. L. , Parlati, F. , Rodriguez, M. L. M. , Shwonek, P. J. , Sjogren, E. B. , Stanton, T. F. , Wang, T. , Yang, J. , Zhao, F. , & Bennett, M. K. (2014). Antitumor activity of the glutaminase inhibitor CB‐839 in triple‐negative breast cancer. Molecular Cancer Therapeutics, 13(4), 890–901. 10.1158/1535-7163.Mct-13-0870|||Han, J. M. , Patterson, S. J. , & Levings, M. K. (2012). The role of the PI3K signaling pathway in CD4(+) T cell differentiation and function. Frontiers in Immunology, 3, 245 10.3389/fimmu.2012.00245|||Heinbokel, T. , Elkhal, A. , Liu, G. , Edtinger, K. , & Tullius, S. G. (2013). Immunosenescence and organ transplantation. Transplantation Reviews, 27(3), 65–75. 10.1016/j.trre.2013.03.001|||Iske, J. , Seyda, M. , Heinbokel, T. , Maenosono, R. , Minami, K. , Nian, Y. , Quante, M. , Falk, C. S. , Azuma, H. , Martin, F. , Passos, J. F. , Niemann, C. U. , Tchkonia, T. , Kirkland, J. L. , Elkhal, A. , & Tullius, S. G. (2020). Senolytics prevent mt‐DNA‐induced inflammation and promote the survival of aged organs following transplantation. Nature Communications, 11(1), 4289 10.1038/s41467-020-18039-x|||Kassel, K. M. , da Au, R. , Higgins, M. J. , Hines, M. , & Graves, L. M. (2010). Regulation of human cytidine triphosphate synthetase 2 by phosphorylation. Journal of Biological Chemistry, 285(44), 33727–33736. 10.1074/jbc.M110.178566|||Kim, J. , & Guan, K. L. (2019). mTOR as a central hub of nutrient signalling and cell growth. Nature Cell Biology, 21(1), 63–71. 10.1038/s41556-018-0205-1|||Kouidhi, S. , Elgaaied, A. B. , & Chouaib, S. (2017). Impact of metabolism on T‐cell differentiation and function and cross talk with tumor microenvironment. Frontiers in Immunology, 8, 270 10.3389/fimmu.2017.00270|||Krenzien, F. , ElKhal, A. , Quante, M. , Rodriguez Cetina Biefer, H. , Hirofumi, U. , Gabardi, S. , & Tullius, S. G. (2015). A rationale for age‐adapted immunosuppression in organ transplantation. Transplantation, 99(11), 2258–2268. 10.1097/tp.0000000000000842|||Krenzien, F. , Quante, M. , Heinbokel, T. , Seyda, M. , Minami, K. , Uehara, H. , Biefer, H. R. C. , Schuitenmaker, J. M. , Gabardi, S. , Splith, K. , Schmelzle, M. , Petrides, A. K. , Azuma, H. , Pratschke, J. , Li, X. C. , ElKhal, A. , & Tullius, S. G. (2017). Age‐dependent metabolic and immunosuppressive effects of tacrolimus. American Journal of Transplantation, 17(5), 1242–1254. 10.1111/ajt.14087|||Lee, C.‐F. , Lo, Y.‐C. , Cheng, C.‐H. , Furtmüller, G. J. , Oh, B. , Andrade‐Oliveira, V. , Thomas, A. G. , Bowman, C. E. , Slusher, B. S. , Wolfgang, M. J. , Brandacher, G. , & Powell, J. D. (2015). Preventing allograft rejection by targeting immune metabolism. Cell Reports, 13(4), 760–770. 10.1016/j.celrep.2015.09.036|||Lemberg, K. M. , Vornov, J. J. , Rais, R. , & Slusher, B. S. (2018). We're not "DON" yet: Optimal dosing and prodrug delivery of 6‐diazo‐5‐oxo‐L‐norleucine. Molecular Cancer Therapeutics, 17(9), 1824–1832. 10.1158/1535-7163.Mct-17-1148|||Leontieva, O. V. , Paszkiewicz, G. M. , & Blagosklonny, M. V. (2012). Mechanistic or mammalian target of rapamycin (mTOR) may determine robustness in young male mice at the cost of accelerated aging. Aging (Albany NY), 4(12), 899–916. 10.18632/aging.100528|||Leung, S. , Smith, D. , Myc, A. , Morry, J. , & Baker, J. R., Jr. (2013). OT‐II TCR transgenic mice fail to produce anti‐ovalbumin antibodies upon vaccination. Cellular Immunology, 282(2), 79–84. 10.1016/j.cellimm.2012.12.006|||Liu, C. , Chapman, N. M. , Karmaus, P. W. , Zeng, H. , & Chi, H. (2015). mTOR and metabolic regulation of conventional and regulatory T cells. Journal of Leukocyte Biology, 97(5), 837–847. 10.1189/jlb.2RI0814-408R|||Lombardi, A. , Trimarco, B. , Iaccarino, G. , & Santulli, G. (2017). Impaired mitochondrial calcium uptake caused by tacrolimus underlies beta‐cell failure. Cell Communication and Signaling, 15(1), 47 10.1186/s12964-017-0203-0|||Martin, E. , Minet, N. , Boschat, A.‐C. , Sanquer, S. , Sobrino, S. , Lenoir, C. , de Villartay, J. P. , Leites‐de‐Moraes, M. , Picard, C. , Soudais, C. , Bourne, T. , Hambleton, S. , Hughes, S. M. , Wynn, R. F. , Briggs, T. A. , Patel, S. , Lawrence, M. G. , Fischer, A. , Arkwright, P. D. , & Latour, S. (2020). Impaired lymphocyte function and differentiation in CTPS1‐deficient patients result from a hypomorphic homozygous mutation. JCI Insight, 5(5), e133880 10.1172/jci.insight.133880|||Martin, E. , Palmic, N. , Sanquer, S. , Lenoir, C. , Hauck, F. , Mongellaz, C. , Fabrega, S. , Nitschké, P. , Esposti, M. D. , Schwartzentruber, J. , Taylor, N. , Majewski, J. , Jabado, N. , Wynn, R. F. , Picard, C. , Fischer, A. , Arkwright, P. D. , & Latour, S. (2014). CTP synthase 1 deficiency in humans reveals its central role in lymphocyte proliferation. Nature, 510(7504), 288–292. 10.1038/nature13386|||Miller, R. A. , Shi, Y. , Lu, W. , Pirman, D. A. , Jatkar, A. , Blatnik, M. , Wu, H. , Cárdenas, C. , Wan, M. , Foskett, J. K. , Park, J. O. , Zhang, Y. , Holland, W. L. , Rabinowitz, J. D. , & Birnbaum, M. J. (2018). Targeting hepatic glutaminase activity to ameliorate hyperglycemia. Nature Medicine, 24(4), 518–524. 10.1038/nm.4514|||Mognol, G. P. , de Araujo‐Souza, P. S. , Robbs, B. K. , Teixeira, L. K. , & Viola, J. P. (2012). Transcriptional regulation of the c‐Myc promoter by NFAT1 involves negative and positive NFAT‐responsive elements. Cell Cycle, 11(5), 1014–1028. 10.4161/cc.11.5.19518|||Newton, R. , Priyadharshini, B. , & Turka, L. A. (2016). Immunometabolism of regulatory T cells. Nature Immunology, 17(6), 618–625. 10.1038/ni.3466|||Oberhuber, R. , Heinbokel, T. , Cetina Biefer, H. R. , Boenisch, O. , Hock, K. , Bronson, R. T. , & Tullius, S. G. (2015). CD11c+ dendritic cells accelerate the rejection of older cardiac transplants via interleukin‐17A. Circulation, 132(2), 122–131. 10.1161/circulationaha.114.014917|||Pereira, M. J. , Palming, J. , Rizell, M. , Aureliano, M. , Carvalho, E. , Svensson, M. K. , & Eriksson, J. W. (2014). Cyclosporine A and tacrolimus reduce the amount of GLUT4 at the cell surface in human adipocytes: increased endocytosis as a potential mechanism for the diabetogenic effects of immunosuppressive agents. Journal of Clinical Endocrinology and Metabolism, 99(10), E1885–1894. 10.1210/jc.2014-1266|||Quante, M. , Heinbokel, T. , Edtinger, K. , Minami, K. , Uehara, H. , Nian, Y. , & Tullius, S. G. (2018). Rapamycin prolongs graft survival and induces CD4+IFN‐gamma+IL‐10+ regulatory type 1 cells in old recipient mice. Transplantation, 102(1), 59–69. 10.1097/tp.0000000000001902|||Ricciardi, S. , Manfrini, N. , Alfieri, R. , Calamita, P. , Crosti, M. C. , Gallo, S. , Müller, R. , Pagani, M. , Abrignani, S. , & Biffo, S. (2018). The translational machinery of human CD4(+) T cells is poised for activation and controls the switch from quiescence to metabolic remodeling. Cell Metabolism, 28(6), 895–906.e895. 10.1016/j.cmet.2018.08.009|||Rodriguez‐Sanchez, I. , Schafer, X. L. , Monaghan, M. , & Munger, J. (2019). The human cytomegalovirus UL38 protein drives mTOR‐independent metabolic flux reprogramming by inhibiting TSC2. PLoS Pathogens, 15(1), e1007569 10.1371/journal.ppat.1007569|||Scalea, J. R. , Tomita, Y. , Lindholm, C. R. , & Burlingham, W. (2016). Transplantation tolerance induction: cell therapies and their mechanisms. Frontiers in Immunology, 7, 87 10.3389/fimmu.2016.00087|||Shelton, L. M. , Huysentruyt, L. C. , & Seyfried, T. N. (2010). Glutamine targeting inhibits systemic metastasis in the VM‐M3 murine tumor model. International Journal of Cancer, 127(10), 2478–2485. 10.1002/ijc.25431|||Sinclair, L. V. , Rolf, J. , Emslie, E. , Shi, Y. B. , Taylor, P. M. , & Cantrell, D. A. (2013). Control of amino‐acid transport by antigen receptors coordinates the metabolic reprogramming essential for T cell differentiation. Nature Immunology, 14(5), 500–508. 10.1038/ni.2556|||Vaeth, M. , Maus, M. , Klein‐Hessling, S. , Freinkman, E. , Yang, J. , Eckstein, M. , Cameron, S. , Turvey, S. E. , Serfling, E. , Berberich‐Siebelt, F. , Possemato, R. , & Feske, S. (2017). Store‐operated Ca(2+) entry controls clonal expansion of T cells through metabolic reprogramming. Immunity, 47(4), 664–679.e666. 10.1016/j.immuni.2017.09.003|||van der Windt, G. J. , & Pearce, E. L. (2012). Metabolic switching and fuel choice during T‐cell differentiation and memory development. Immunological Reviews, 249(1), 27–42. 10.1111/j.1600-065X.2012.01150.x|||Waickman, A. T. , & Powell, J. D. (2012). mTOR, metabolism, and the regulation of T‐cell differentiation and function. Immunological Reviews, 249(1), 43–58. 10.1111/j.1600-065X.2012.01152.x|||Wang, R. , Dillon, C. P. , Shi, L. Z. , Milasta, S. , Carter, R. , Finkelstein, D. , McCormick, L. L. , Fitzgerald, P. , Chi, H. , Munger, J. , & Green, D. R. (2011). The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity, 35(6), 871–882. 10.1016/j.immuni.2011.09.021|||Weyand, C. M. , Yang, Z. , & Goronzy, J. J. (2014). T‐cell aging in rheumatoid arthritis. Current Opinion in Rheumatology, 26(1), 93–100. 10.1097/bor.0000000000000011|||Yang, L. , Venneti, S. , & Nagrath, D. (2017). Glutaminolysis: A hallmark of cancer metabolism. Annual Review of Biomedical Engineering, 19, 163–194. 10.1146/annurev-bioeng-071516-044546|||Yang, Z. , Shen, Y. , Oishi, H. , Matteson, E. L. , Tian, L. , Goronzy, J. J. , & Weyand, C. M. (2016). Restoring oxidant signaling suppresses proarthritogenic T cell effector functions in rheumatoid arthritis. Science Translational Medicine, 8(331), 331ra338 10.1126/scitranslmed.aad7151|||Yin, Y. , Choi, S. C. , Xu, Z. , Zeumer, L. , Kanda, N. , Croker, B. P. , & Morel, L. (2016). Glucose oxidation is critical for CD4+ T cell activation in a mouse model of systemic lupus erythematosus. Journal of Immunology, 196(1), 80–90. 10.4049/jimmunol.1501537|||Zhang, J. , & Zhang, Q. (2019). Using seahorse machine to measure OCR and ECAR in cancer cells. Methods in Molecular Biology, 1928, 353–363. 10.1007/978-1-4939-9027-6_18