Changes of T-cell Immunity Over a Lifetime.
Authors:
Journal: Transplantation
Publication Type: Journal Article
Date: 2019
DOI: NIHMS1529225
ID: 31107822
Abstract
T-cell immunity undergoes a complex and continuous remodeling with aging. Understanding those dynamics is essential in refining immunosuppression. Aging is linked to phenotypic and metabolic changes in T-cell immunity, many resulting into impaired function and compromised effectiveness. Those changes may impact clinical immunosuppression with evidences suggesting age-specific efficacies of some (CNI and mammalian target of rapamycin inhibitors) but not necessarily all immunosuppressants. Metabolic changes of T cells with aging have only recently been appreciated and may provide novel ways of immunosuppression. Here, we provide an update on changes of T-cell immunity in aging.
Chemical List
- Calcineurin Inhibitors|||Immunosuppressive Agents|||TOR Serine-Threonine Kinases
Reference List
- Martins PNA, Tullius SG, Markmann JF. Immunosenescence and immune response in organ transplantation. Int Rev Immunol. 2014;33(3):162–173. doi:10.3109/08830185.2013.829469|||Krenzien F, ElKahl A, Quante M, et al. A Rationale for Age-Adapted Immunosuppression in Organ Transplantation. Transplantation. 2015;99(11):2258–2268. doi:10.1097/TP.0000000000000842|||Tu W, Rao S. Mechanisms Underlying T Cell Immunosenescence: Aging and Cytomegalovirus Infection. Front Microbiol. 2016;7:2111. doi:10.3389/fmicb.2016.02111|||Cossarizza A, Ortolani C, Monti D, et al. Cytometric analysis of immunosenescence. Cytometry. 1997;27(4):297–313.|||Linton PJ, Dorshkind K. Age-related changes in lymphocyte development and function. Nat Immunol. 2004;5:133–139. doi:10.1038/ni1033|||Pallikkuth S, de Armas L, Rinaldi S, et al. T Follicular Helper Cells and B Cell Dysfunction in Aging and HIV-1 Infection. Front Immunol. 2017;8:1380. doi:10.3389/fimmu.2017.01380|||Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell. 2010;140(6):883–899. doi:10.1016/j.cell.2010.01.025|||Koch S, Larbi A, Dehovanessian E, et al. Multiparameter flow cytometric analysis of CD4 and CD8 T cell subsets in young and old people. Immun Ageing. 2008;5:6. doi:10.1186/1742-4933-5-6|||Heinbokel T, Elkhal A, Liu G, et al. G. Immunosenescence and organ transplantation. Transplant Rev (Orlando). 2013;27(3):65–75. doi:10.1016/j.trre.2013.03.001|||Palmer S, Albergante L, Blackburn CC, et al. Thymic involution and rising disease incidence with age. Proc Natl Acad Sci U S A. 2018;115(8):1883–1888. doi:10.1073/pnas.1714478115|||Lakkis FG, Sayegh MH. Memory T cells: a hurdle to immunologic tolerance. J Am Soc Nephrol. 2003;14(9):2402–2410.|||Geiger H, Van Zant G. The aging of lympho-hematopoietic stem cells. Nat Immunol. 2002;3(4):329–333. doi:10.1038/ni0402-329|||Macallan DC, Borghans JAM, Asquith B. Human T Cell Memory: A Dynamic View. Vaccines. 2017;5(1):5. doi:10.3390/vaccines5010005|||Hammarlund E, Lewis MW, Hansen SG, et al. Duration of antiviral immunity after smallpox vaccination. Nat Med. 2003;9:1131–1137. doi:10.1038/nm917|||Appay V, Sauce D. Naive T cells: the crux of cellular immune aging? Exp Gerontol. 2014;54:90–93. doi:10.1016/j.exger.2014.01.003|||Sachsenberg N, Perelson AS, Yerly S, et al. Turnover of CD4+ and CD8+ T lymphocytes in HIV-1 infection as measured by Ki-67 antigen. J Exp Med. 1998;187(8):1295–1303.|||Hazenberg MD, Stuart JW, Otto SA, et al. T-cell division in human immunodeficiency virus (HIV)-1 infection is mainly due to immune activation: a longitudinal analysis in patients before and during highly active antiretroviral therapy (HAART). Blood. 2000;95(1):249–255.|||Kohler S, Wagner U, Pierer M, et al. Post-thymic in vivo proliferation of naive CD4+ T cells constrains the TCR repertoire in healthy human adults. Eur J Immunol. 2005;35(6):1987–1994. doi:10.1002/eji.200526181|||Naylor K, Li G, Vallejo AN, et al. The influence of age on T cell generation and TCR diversity. J Immunol. 2005;174(11):7446–7452.|||Zhang T, Fresnay S, Welty E, et al. Selective CD28 blockade attenuates acute and chronic rejection of murine cardiac allografts in a CTLA-4-dependent manner. Am J Transplant. 2011;11(8):1599–1609. doi:10.1111/j.1600-6143.2011.03624.x|||Weng NP, Akbar AN, Goronzy J. CD28(−) T cells: their role in the age-associated decline of immune function. Trends Immunol. 2009;30(7):306–312. doi:10.1016/j.it.2009.03.013|||Vallejo AN. CD28 extinction in human T cells: altered functions and the program of T-cell senescence. Immunol Rev. 2005;205(1):158–169. doi:10.1111/j.0105-2896.2005.00256.x|||Seyda M, Elkhal A, Quante M, et al. T Cells Going Innate. Trends Immunol. 2016;37(8):546–556. doi:10.1016/j.it.2016.06.004|||Vallejo AN, Brandes JC, Weyand CM, et al. Modulation of CD28 expression: distinct regulatory pathways during activation and replicative senescence. J Immunol. 1999;162(11):6572–6579.|||Bryl E, Witkowski JM. Decreased proliferative capability of CD4(+) cells of elderly people is associated with faster loss of activation-related antigens and accumulation of regulatory T cells. Exp Gerontol. 2004;39(4):587–595. doi:10.1016/j.exger.2003.10.029|||Chen G, Lustig A, Weng NP. T cell aging: a review of the transcriptional changes determined from genome-wide analysis. Front Immunol. 2013;4:121. doi:10.3389/fimmu.2013.00121|||Buck MD, O’Sullivan D, Pearce EL. T cell metabolism drives immunity. J Exp Med. 2015;212(9):1345–1360. doi:10.1084/jem.20151159|||Yang Z, Fujii H, Mohan SV, et al. Phosphofructokinase deficiency impairs ATP generation, autophagy, and redox balance in rheumatoid arthritis T cells. J Exp Med. 2013;210(10):2119–2134. doi:10.1084/jem.20130252|||Patsoukis N, Bardhan K, Chatterjee P, et al. PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation. Nat Commun. 2015;6:6692. doi:ARTN 6692 10.1038/ncomms7692|||Sena LA, Li S, Jairaman A, et al. Mitochondria are required for antigen-specific T cell activation through reactive oxygen species signaling. Immunity. 2013;38(2):225–236. doi:10.1016/j.immuni.2012.10.020|||Genova ML, Lenaz G. The Interplay Between Respiratory Supercomplexes and ROS in Aging. Antioxid Redox Signal. 2015;23(3):208–238. doi:10.1089/ars.2014.6214|||Ogasawara Y, Nakayama K, Tarnowka M, et al. Mitochondrial DNA spectra of single human CD34+ cells, T cells, B cells, and granulocytes. Blood. 2005;106(9):3271–3284. doi:10.1182/blood-2005-01-0150|||Weyand CM, Yang Z, Goronzy JJ. T-cell aging in rheumatoid arthritis. Curr Opin Rheumatol. 2014;26(1):93–100. doi:10.1097/BOR.0000000000000011|||Mattoo H, Faulkner M, Kandpal U, et al. Naive CD4 T cells from aged mice show enhanced death upon primary activation. Int Immunol. 2009;21(11):1277–1289. doi:10.1093/intimm/dxp094|||Balaban RS, Nemoto S, Finkel T. Mitochondria, oxidants, and aging. Cell. 2005;120(4):483–495. doi:10.1016/j.cell.2005.02.001|||Yang Z, Shen Y, Oishi H, et al. Restoring oxidant signaling suppresses proarthritogenic T cell effector functions in rheumatoid arthritis. Sci Transl Med. 2016;8(331):331ra338. doi:10.1126/scitranslmed.aad7151|||Lohmiller JJ, Roellich KM, Toledano A, et al. Aged murine T-lymphocytes are more resistant to oxidative damage due to the predominance of the cells possessing the memory phenotype. J Gerontol A Biol Sci Med Sci. 1996;51(2):B132–140.|||Goronzy JJ, Li G, Yu M, et al. Signaling pathways in aged T cells - a reflection of T cell differentiation, cell senescence and host environment. Semin Immunol. 2012;24(5):365–372. doi:10.1016/j.smim.2012.04.003|||Finkel T Signal transduction by reactive oxygen species. J Cell Biol. 2011;194(1):7–15. doi:10.1083/jcb.201102095|||Di Meo S, Reed TT, Venditti P, et al. Harmful and Beneficial Role of ROS 2017. Oxid Med Cell Longev. 2018;2018:5943635. doi:10.1155/2018/5943635|||Huang H, Patel DD, Manton KG. The immune system in aging: roles of cytokines, T cells and NK cells. Front Biosci. 2005;10:192–215.|||Zanni F, Vescovini R, Biasini C, et al. Marked increase with age of type 1 cytokines within memory and effector/cytotoxic CD8+ T cells in humans: a contribution to understand the relationship between inflammation and immunosenescence. Exp Gerontol. 2003;38(9):981–987.|||Yung R, Powers D, Johnson K, et al. Mechanisms of drug-induced lupus. II. T cells overexpressing lymphocyte function-associated antigen 1 become autoreactive and cause a lupuslike disease in syngeneic mice. J Clin Invest. 1996;97(12):2866–2871. doi:10.1172/JCI118743|||Bachmann MF, Oxenius A. Interleukin 2: from immunostimulation to immunoregulation and back again. EMBO Reports. 2007;8(12):1142–1148. doi:10.1038/sj.embor.7401099|||Shen H, Tesar BM, Du W, et al. Aging impairs recipient T cell intrinsic and extrinsic factors in response to transplantation. PLoS One. 2009;4(1):e4097. doi:10.1371/journal.pone.0004097|||Elrefaei M, Blank KJ, Murasko DM. Decreased IL-2, IFN-gamma, and IL-10 production by aged mice during the acute phase of E55+ retrovirus infection. Virology. 2002;299(1):8–19.|||Gong Z, Liu T, Wan Y, et al. Decreased c-rel activation contributes to aberrant interleukin-2 expression in CD4+T cells of aged rats. Mol Immunol. 2014;61:1–6. doi:10.1016/j.molimm.2014.04.010|||Haynes L, Linton PJ, Eaton SM, et al. Interleukin 2, but not other common gamma chain-binding cytokines, can reverse the defect in generation of CD4 effector T cells from naive T cells of aged mice. J Exp Med. 1999;190(7):1013–1024.|||Seyda M, Quante M, Uehara H, et al. Immunosenescence in renal transplantation: a changing balance of innate and adaptive immunity. Curr Opin Organ Transplant. 2015;20(4):417–423. doi:10.1097/MOT.0000000000000210|||Shearer GM. Th1/Th2 changes in aging. Mech Ageing Dev. 1997;94(1–3):1–5.|||Uciechowski P, Kahmann L, Plümäkers B, et al. TH1 and TH2 cell polarization increases with aging and is modulated by zinc supplementation. Exp Gerontol. 2008;43(5):493–498. doi:10.1016/j.exger.2007.11.006|||Li SP, Miller RA. Age-associated decline in IL-4 production by murine T lymphocytes in extended culture. Cell Immunol. 1993;151(1):187–195. doi:10.1006/cimm.1993.1230|||Tarazona R, DelaRosa O, Alonso C, et al. Increased expression of NK cell markers on T lymphocytes in aging and chronic activation of the immune system reflects the accumulation of effector/senescent T cells. Mech Ageing Dev. 2000;121(1–3):77–88.|||Effros RB, Cai Z, Linton PJ. CD8 T cells and aging. Crit Rev Immunol. 2003;23(1–2):45–64.|||Bennett SRM, Carbone FR, Karamalis F, et al. Induction of a CD8+ cytotoxic T lymphocyte response by cross-priming requires cognate CD4+ T cell help. J Exp Med. 1997;186(1):65–70.|||Dias S, D’Amico A, Cretney E, et al. Effector Regulatory T Cell Differentiation and Immune Homeostasis Depend on the Transcription Factor Myb. Immunity. 2017;46(1):78–91. doi:10.1016/j.immuni.2016.12.017|||Buckner JH. Mechanisms of impaired regulation by CD4(+)CD25(+)FOXP3(+) regulatory T cells in human autoimmune diseases. Nat Rev Immunol. 2010;10(12):849–859. doi:10.1038/nri2889|||Qian T, Ricordi C, Inverardi L, et al. Intrathymic tolerance and age. Transplant Proc. 1995;27(6):3391.|||Nobori S, Shimizu A, Okumi M, et al. Thymic rejuvenation and the induction of tolerance by adult thymic grafts. Proc Natl Acad Sci U S A. 2006;103(50):19081–19086. doi:10.1073/pnas.0605159103|||Zhao L, Liguang S, Wang H, et al. Changes of CD4+CD25+Foxp3+ regulatory T cells in aged Balb/c mice. J Leukoc Biol. 2007;81(6):1386–1394. doi:10.1189/jlb.0506364|||Sharma S, Dominguez AL, Lustgarten J High accumulation of T regulatory cells prevents the activation of immune responses in aged animals. J Immunol. 2006;177(12):8348–8355|||Trzonkowski P, Szmit E, Myśliwska J, et al. CD4+CD25+ T regulatory cells inhibit cytotoxic activity of CTL and NK cells in humans-impact of immunosenescence. Clin Immunol. 2006;119(3):307–316. doi:10.1016/j.clim.2006.02.002|||Cello JP. Acquired immunodeficiency syndrome cholangiopathy: spectrum of disease. Am J Med. 1989;86(5):539–546.|||Pahlavani MA, Vargas DM. Age-related decline in activation of calcium/calmodulin-dependent phosphatase calcineurin and kinase CaMK-IV in rat T cells. Mech Ageing Dev. 1999;112(1):59–74.|||Krenzien F, Quante M, Heinbokel T, et al. Age-Dependent Metabolic and Immunosuppressive Effects of Tacrolimus. Am J Transplant. 2017;17(5):1242–1254. doi:10.1111/ajt.14087|||Warrington JS, Greenblatt DJ, von Moltke LL. Age-related differences in CYP3A expression and activity in the rat liver, intestine, and kidney. J Pharmacol Exp Ther. 2004;309(2):720–729. doi:10.1124/jpet.103.061077|||Jacobson PA, Schladt D, Oetting WS, et al. Lower calcineurin inhibitor doses in older compared to younger kidney transplant recipients yield similar troughs. Am J Transplant. 2012;12(12):3326–3336. doi:10.1111/j.1600-6143.2012.04232.x|||Patel CH, Powell JD. Targeting T cell metabolism to regulate T cell activation, differentiation and function in disease. Curr Opin Immunol. 2017;46:82–88. doi:10.1016/j.coi.2017.04.006|||Kauffman HM, Cherikh WS, Cheng Y, et al. Maintenance immunosuppression with target-of-rapamycin inhibitors is associated with a reduced incidence of de novo malignancies. Transplantation. 2005;80(7):883–889.|||Fischer L, Klempnauer J, Beckemaum S, et al. A randomized, controlled study to assess the conversion from calcineurin-inhibitors to everolimus after liver transplantation--PROTECT. Am J Transplant. 2012;12(7):1855–1865. doi:10.1111/j.1600-6143.2012.04049.x|||Vincenti F, Schena FP, Paraskevas S, et al. A randomized, multicenter study of steroid avoidance, early steroid withdrawal or standard steroid therapy in kidney transplant recipients. Am J Transplant. 2008;8(2):307–316. doi:10.1111/j.1600-6143.2007.02057.x|||Quante M, Heinokel T, Edtinger K, et al. Rapamycin Prolongs Graft Survival and Induces CD4+IFN-gamma+IL-10+ Regulatory Type 1 Cells in Old Recipient Mice. Transplantation. 2018;102(1):59–69. doi:10.1097/TP.0000000000001902|||Beyersdorf N, Kerkau T, Hunig T CD28 co-stimulation in T-cell homeostasis: a recent perspective. Immunotargets Ther. 2015;4:111–122. doi:10.2147/ITT.S61647|||Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009;324(5930):1029–1033. doi:10.1126/science.1160809|||Le Bourgeois T, Strauss L, Aksoylar HI et al. Targeting T Cell Metabolism for Improvement of Cancer Immunotherapy. Front Oncol. 2018;8:237. doi:10.3389/fonc.2018.00237|||Wang R, Dillon CP, Shi LZ, et al. The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity. 2011;35(6):871–882. doi:10.1016/j.immuni.2011.09.021|||Huynh A, DuPage M, Priyadharshini B, et al. Control of PI(3) kinase in Treg cells maintains homeostasis and lineage stability. Nat Immunol. 2015;16(2):188–196, doi:10.1038/ni.3077|||Wahl DR, Byersdorfer CA, Ferrara JL, et al. Distinct metabolic programs in activated T cells: opportunities for selective immunomodulation. Immunol Rev. 2012;249(1):104–115. doi:10.1111/j.1600-065X.2012.01148.x|||Shi LZ, Wang R, Huang G, et al. HIF1alpha-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. J Exp Med. 2011;208(7):1367–1376. doi:10.1084/jem.20110278|||Li J, Kim SG, Blenis J. Rapamycin: one drug, many effects. Cell Metab. 2014;19(3):373–379. doi:10.1016/j.cmet.2014.01.001|||Zhao Q, Chu Z, Zhu L., et al. 2-Deoxy-d-Glucose Treatment Decreases Anti-inflammatory M2 Macrophage Polarization in Mice with Tumor and Allergic Airway Inflammation. Front Immunol. 2017;8:637. doi:10.3389/fimmu.2017.00637|||Yin Y, Choi SC, Xu Z, et al. Glucose Oxidation Is Critical for CD4+ T Cell Activation in a Mouse Model of Systemic Lupus Erythematosus. J Immunol. 2016;196(1):80–90. doi:10.4049/jimmunol.1501537|||Biondani G, Peyron JF. Metformin, an Anti-diabetic Drug to Target Leukemia. Front Endocrinol (Lausanne). 2018;9:446. doi:10.3389/fendo.2018.00446|||Andrzejewski S, Gravel SP, Pollak M, et al. Metformin directly acts on mitochondria to alter cellular bioenergetics. Cancer Metab. 2014;2:12. doi:10.1186/2049-3002-2-12|||Lee CF, Lo YC, Cheng CH, et al. Preventing Allograft Rejection by Targeting Immune Metabolism. Cell Rep. 2015;13(4):760–770. doi:10.1016/j.celrep.2015.09.036