A fundamental feature of mammalian adaptive immunity is the highly diverse pool of antigen receptors found on lymphocytes. The T-cell receptor and the surface immunoglobulin on B cells facilitate the recognition of foreign structures found on tumors and pathogens that have overwhelmed the defenses of the innate immune system. Because pathogen encounters and neoplasic transformations are inherently unpredictable, an immense lymphocyte receptor repertoire is required to meet all of the possible challenges an organism will face. In young humans, the daily production of naïve B cells from the bone marrow and T cells from the thymus steadily injects the lymphocyte pool with new antigen receptors. Unfortunately, as humans age functional thymic tissue gradually involutes and is replaced by fat. In parallel, the daily production of new naïve T cells declines such that no meaningful thymic T-cell production occurs after the age of fifty. Thus, the T-cell repertoire of an adult human must be maintained for decades in the absence of a replenishing source. Although homeostatic mechanisms are remarkably successful at maintaining the T-cell repertoire for many years, obvious changes begin to emerge with advanced age. Most strikingly, the naïve CD4 T cells that remain after the age of 65 undergo a sudden and dramatic collapse of T-cell receptor diversity. Naïve CD8 T cells may experience an earlier and more gradual diversity loss, although direct evidence for this is not yet available. A steadily expanding memory population maintains total T-cell numbers despite the decline in naïve T cells. Among these memory cells, an increasing percentage acquires a terminally differentiated phenotype characterized by abnormal expression of regulatory receptors and resistance to apoptosis. Oligoclonal populations accumulate after a lifetime of repeated challenges such as chronic infections, leading to a contracted memory repertoire. Although the consequences of repertoire contraction are not yet known, this phenomenon may have important implications for the health of the ever growing elderly population.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Bhandoola A, H von Boehmer, HT Petrie, JC Zuniga-Pflucker (2007) Commitment and developmental potential of extrathymic and intrathymic T-cell precursors: plenty to choose from. Immunity 26:678–689
Blom B, P Res, E Noteboom, K. Weijer, H Spits (1997) Prethymic CD34 progenitors capable of developing into T cells are not committed to the T-cell lineage. J Immunol 158:3571–3577
Galy A, S Verma, A Barcena, H Spits (1993) Precursors of CD3CD4CD8 cells in the human thymus are defined by expression of CD34. Delineation of early events in human thymic development. J Exp Med 178:391–401
Blom B, MC Verschuren, MH Heemskerk, AQ Bakker, EJ van Gastel-Mol, IL Wolvers-Tettero, JJ van Dongen, H Spits (1999) TCR gene rearrangements and expression of the pre-T-cell receptor complex during human T-cell differentiation. Blood 93:3033–3043
Pui JC, D Allman, L Xu, S DeRocco, FG Karnell, S Bakkour, JY Lee, T Kadesch, RR Hardy, JC Aster, WS Pear (1999) Notch1 expression in early lymphopoiesis influences B versus T lineage determination. Immunity 11:299–308
van Dongen JJ, WM Comans-Bitter, L Wolvers-Tettero, J Borst (1990) Development of human T-lymphocytes and their thymus-dependency. Thymus 16:207–234
Davis MM, PJ Bjorkman (1988) T-cell antigen receptor genes and T-cell recognition. Nature 334:395–402
Spits H (2002) Development of alphabeta T cells in the human thymus. Nat Rev 2:760–772
Wilson A, W Held, HR MacDonald (1994) Two waves of recombinase gene expression in developing thymocytes. J Exp Med 179:1355–1360
Krangel MS (2003) Gene segment selection in V(D)J recombination: accessibility and beyond. Nat Immunol 4:624–630
Benedict CL, S Gilfillan, TH Thai, JF Kearney (2000) Terminal deoxynucleotidyl transferase and repertoire development. Immunol Rev 175:150–157
von Boehmer H (2005) Unique features of the pre-T-cell receptor alpha-chain: not just a surrogate. Nat Rev 5:571–577
Trigueros C, AR Ramiro, YR Carrasco, VG de Yebenes, JP Albar, ML Toribio (1998) Identification of a late stage of small noncycling pTalpha—pre-T cells as immediate precursors of T-cell receptor alpha/beta thymocytes. J Exp Med 188:1401–1412
Petrie HT, F Livak, DG Schatz, A Strasser, IN Crispe, K Shortman (1993) Multiple rearrangements in T-cell receptor alpha chain genes maximize the production of useful thymocytes. J Exp Med 178:615–622
Brandle D, C Muller, T Rulicke, H Hengartner, H Pircher (1992) Engagement of the T-cell receptor during positive selection in the thymus down-regulates RAG-1 expression. Proc Natl Acad Sci U S A 89:9529–9533
Palmer E 2003 Negative selection—clearing out the bad apples from the T-cell repertoire. Nat Rev 3:383–391
Fagnoni FF, R Vescovini, G Passeri, G Bologna, M Pedrazzoni, G Lavagetto, A Casti, C Franceschi, M Passeri, P Sansoni (2000) Shortage of circulating naive CD8() T cells provides new insights on immunodeficiency in aging. Blood 95:2860–2868
Hong MS, JM Dan, JY Choi, I Kang (2004) Age-associated changes in the frequency of naive, memory and effector CD8 T cells. Mech Ageing Dev 125:615–618
Naylor K, G Li, AN Vallejo, WW Lee, K Koetz, E Bryl, J Witkowski, J Fulbright, CM Weyand, JJ Goronzy (2005) The influence of age on T-cell generation and TCR diversity. J Immunol 174:7446–7452
Sallusto F, D Lenig, R Forster, M Lipp, A Lanzavecchia (1999) Two subsets of memory Tlymphocytes with distinct homing potentials and effector functions. Nature 401:708–712
Lanzavecchia A, F Sallusto (2000) Dynamics of T-lymphocyte responses: intermediates, effectors, and memory cells. Science (New York, N.Y) 290:92–97
Jacob J, D Baltimore (1999) Modelling T-cell memory by genetic marking of memory T cells in vivo. Nature 399:593–597
Opferman JT, BT Ober, PG Ashton-Rickardt (1999) Linear differentiation of cytotoxic effectors into memory T-lymphocytes. Science (New York, N.Y) 283:1745–1748
Faint JM, NE Annels, SJ Curnow, P Shields, D Pilling, A D Hislop, L Wu, AN Akbar, CD Buckley, PA Moss, DH Adams, A B Rickinson, M Salmon (2001) Memory T cells constitute a subset of the human CD8CD45RA pool with distinct phenotypic and migratory characteristics. J Immunol 167:212–220
Van Den Beemd R, PP Boor, EG van Lochem, WC Hop, AW Langerak, IL Wolvers-Tettero, H Hooijkaas, JJ van Dongen (2000) Flow cytometric analysis of the Vbeta repertoire in healthy controls. Cytometry 40:336–345
Hadrup SR, J Strindhall, T Kollgaard, T Seremet, B Johansson, G Pawelec, P thor Straten, A Wikby (2006) Longitudinal studies of clonally expanded CD8 T cells reveal a repertoire shrinkage predicting mortality and an increased number of dysfunctional cytomegalovirusspecific T cells in the very elderly. J Immunol 176:2645–2653
Even J, A Lim, I Puisieux, L Ferradini, PY Dietrich, A Toubert, T Hercend, F Triebel, C Pannetier, P Kourilsky (1995) T-cell repertoires in healthy and diseased human tissues analysed by T-cell receptor beta-chain CDR3 size determination: evidence for oligoclonal expansions in tumours and inflammatory diseases. Res Immunol 146:65–80
Arstila T P, A Casrouge, V Baron, J Even, J Kanellopoulos, P Kourilsky (1999) A direct estimate of the human alphabeta T-cell receptor diversity. Science New York, N.Y 286:958–961
Wagner UG, K Koetz, CM Weyand, JJ Goronzy (1998) Perturbation of the T-cell repertoire in rheumatoid arthritis. Proc Natl Acad Sci U S A 95:14447–14452
Taub DD, DL Longo (2005) Insights into thymic aging and regeneration. Immunol Rev 205:72–93
Livak F, DG Schatz (1996) T-cell receptor alpha locus V(D)J recombination by-products are abundant in thymocytes and mature T cells. Mol Cell Biol 16:609–618
de Villartay JP, RD Hockett, D Coran, SJ Korsmeyer, DI Cohen (1988) Deletion of the human T-cell receptor delta-gene by a site-specific recombination. Nature 335:170–174
Hazenberg MD, MC Verschuren, D Hamann, F Miedema, JJ van Dongen (2001) T-cell receptor excision circles as markers for recent thymic emigrants: basic aspects, technical approach, and guidelines for interpretation. J Mol Med (Berlin, Germany) 79:631–640
Douek DC, RD McFarland, PH Keiser, EA Gage, JM Massey, BF Haynes, MA Polis, AT Haase, MB Feinberg, JL Sullivan, BD Jamieson, JA Zack, LJ Picker, R A Koup (1998) Changes in thymic function with age and during the treatment of HIV infection. Nature 396:690–695
Koetz K, E Bryl, K Spickschen, WM O’Fallon, JJ Goronzy, CM Weyand (2000) T-cell homeostasis in patients with rheumatoid arthritis. Proc Natl Acad Sci U S A 97:9203–9208
Poulin JF, MN Viswanathan, JM Harris, KV Komanduri, E Wieder, N Ringuette, M Jenkins, J M McCune, R P Sekaly (1999) Direct evidence for thymic function in adult humans. J Exp Med 190:479–486
Flores KG, J Li, GD Sempowski, BF Haynes, L P Hale (1999) Analysis of the human thymic perivascular space during aging. J Clin Invest 104:1031–1039
Steinmann GG, B Klaus, HK Muller-Hermelink (1985) The involution of the ageing human thymic epithelium is independent of puberty. A morphometric study. Scand J Immunol 22:563–575
Jamieson BD, DC Douek, S Killian, LE Hultin, DD Scripture-Adams, JV Giorgi, D Marelli, R A Koup, J A Zack (1999) Generation of functional thymocytes in the human adult. Immunity 10:569–575
Hakim FT, SA Memon, R Cepeda, EC Jones, CK Chow, C Kasten-Sportes, J Odom, BA Vance, BL Christensen, CL Mackall, RE Gress (2005) Age-dependent incidence, time course, and consequences of thymic renewal in adults. J Clin Invest 115:930–939
Kimmig S, G K Przybylski, CA Schmidt, KLaurisch, B Mowes, A Radbruch, A Thiel (2002) Two subsets of naive T-helper cells with distinct T-cell receptor excision circle content in human adult peripheral blood. J Exp Med 195:789–794
Gerdes J, H Lemke, H Baisch, HH Wacker, U Schwab, H Stein (1984) Cell cycle analysis of a cell proliferation-associated human nuclear antigen defined by the monoclonal antibody Ki- 67. J Immunol 133:1710–1715
Betts MR, JM Brenchley, DA Price, SC De Rosa, DC Douek, M Roederer, RA Koup (2003) Sensitive and viable identification of antigen-specific CD8 T cells by a flow cytometric assay for degranulation. J Immunol Methods 281:65–78
Hazenberg MD, JW Stuart, SA Otto, JC Borleffs, CA Boucher, RJ de Boer, F Miedema, D Hamann (2000) 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 95:249–255
Schonland SO, JK Zimmer, CM Lopez-Benitez, T Widmann, KD Ramin, JJ Goronzy, CM Weyand (2003) Homeostatic control of T-cell generation in neonates. Blood 102:1428–1434
Macallan DC, B Asquith, AJ Irvine, DL Wallace, A Worth, H Ghattas, Y Zhang, GE Griffin, DF Tough, P C Beverley (2003) Measurement and modeling of human T-cell kinetics. Eur J Immunol 33:2316–2326
Macallan DC, CA Fullerton, RA Neese, K Haddock, SS Park, MK Hellerstein (1998) Measurement of cell proliferation by labeling of DNA with stable isotope-labeled glucose: studies in vitro, in animals, and in humans. Proc Natl Acad Sci U S A 95:708–713
Neese RA, LM Misell, S Turner, A Chu, J Kim, D Cesar, R Hoh, F Antelo, A Strawford, JM McCune, M Christiansen, MK Hellerstein (2002) Measurement in vivo of proliferation rates of slow turnover cells by 2H2O labeling of the deoxyribose moiety of DNA. Proc Natl Acad Sci U S A 99:15345–15350
Wallace DL, Y Zhang, H Ghattas, A Worth, A Irvine, AR Bennett, GE Griffin, PC Beverley, DF Tough, DC Macallan. (2004) Direct measurement of T-cell subset kinetics in vivo in elderly men and women. J Immunol 173:1787–1794
Hellerstein M, MB Hanley, D Cesar, S Siler, C Papageorgopoulos, E Wieder, D Schmidt, R Hoh, R Neese, D Macallan, S Deeks, JM McCune (1999) Directly measured kinetics of circulating T-lymphocytes in normal and HIV-1-infected humans. Nat Med 5:83–89
Murray JM, GR Kaufmann, PD Hodgkin, SR Lewin, AD Kelleher, MP Davenport, JJ Zaunders (2003) Naive T cells are maintained by thymic output in early ages but by proliferation without phenotypic change after age twenty. Immunol Cell Biol 81:487–495
Brocker T (1997) Survival of mature CD4 T-lymphocytes is dependent on major histocompatibility complex class II-expressing dendritic cells. J Exp Med 186:1223–1232
Kirberg J, A Berns, H von Boehmer (1997) Peripheral T-cell survival requires continual ligation of the T-cell receptor to major histocompatibility complex-encoded molecules. J Exp Med 186:1269–1275
Tanchot C, FA Lemonnier, B Perarnau, AA Freitas, B Rocha (1997) Differential requirements for survival and proliferation of CD8 naive or memory T cells. Science (New York, N.Y) 276:2057–2062
Murali-Krishna K, LL Lau, S Sambhara, F Lemonnier, J Altman, R Ahmed (1999) Persistence of memory CD8 T cells in MHC class I-deficient mice. Science (New York, N.Y) 286:1377–1381
Ge Q, VP Rao, BK Cho, HN Eisen, J Chen (2001) Dependence of lymphopenia-induced T-cell proliferation on the abundance of peptide/ MHC epitopes and strength of their interaction with T-cell receptors. Proc Natl Acad Sci U S A 98:1728–1733
Wang Q, J Strong, N Killeen (2001) Homeostatic competition among T cells revealed by conditional inactivation of the mouse Cd4 gene. J Exp Med 194:1721–1730
Jameson SC (2002) Maintaining the norm: T-cell homeostasis. Nat Rev 2:547–556
Tan JT, E Dudl, E LeRoy, R Murray, J Sprent, KI Weinberg, C D Surh (2001) IL-7 is critical for homeostatic proliferation and survival of naive T cells. Proc Natl Acad Sci U S A 98:8732–8737
Geginat J, A Lanzavecchia, F Sallusto (2003) Proliferation and differentiation potential of human CD8 memory T-cell subsets in response to antigen or homeostatic cytokines. Blood 101:4260–4266
Hazenberg MD, SA Otto, JW Cohen Stuart, MC Verschuren, JC Borleffs, CA Boucher, RA Coutinho, JM Lange, TF Rinke deWit, A Tsegaye, JJ van Dongen, D Hamann, RJ de Boer, F Miedema (2000) Increased cell division but not thymic dysfunction rapidly affects the T-cell receptor excision circle content of the naive T-cell population in HIV-1 infection. Nat Med 6:1036–1042
Goronzy JJ, WW Lee, CM Weyand (2007) Aging and T-cell diversity. Exp Gerontol 42:400–406
Czesnikiewicz-Guzik M, WW Lee, D Cui, Y Hiruma, DL Lamar, ZZ Yang, JG Ouslander, C M Weyand, JJ Goronzy (2008) T-cell subset-specific susceptibility to aging. Clin Immunol 127:107–118
Effros RB, N Boucher, V Porter, X Zhu, C Spaulding, RL Walford, M Kronenberg, D Cohen, F Schachter (1994) Decline in CD28 T cells in centenarians and in long-term T-cell cultures: a possible cause for both in vivo and in vitro immunosenescence. Exp Gerontol 29:601–609
Colonna M, F Navarro, T Bellon, M Llano, P Garcia, J Samaridis, L Angman, M Cella, M Lopez-Botet (1997) A common inhibitory receptor for major histocompatibility complex class I molecules on human lymphoid and myelomonocytic cells. J Exp Med 186:1809–1818
Jankovic V, I Messaoudi, J Nikolich-Zugich (2003) Phenotypic and functional T-cell aging in rhesus macaques (Macaca mulatta): differential behavior of CD4 and CD8 subsets. Blood 102:3244–3251
Ricalton NS, C Roberton, JM Norris, M Rewers, RF Hamman, BL Kotzin (1998) Prevalence of CD8 T-cell expansions in relation to age in healthy individuals. J Gerontol 53: B196–B203
Wack A, A Cossarizza, S Heltai, D Barbieri, S D’Addato, C Fransceschi, P Dellabona, G Casorati (1998) Age-related modifications of the human alphabeta T-cell repertoire due to different clonal expansions in the CD4 and CD8 subsets. Int Immunol 10:1281–1288
Goronzy JJ, CM Weyand (2005) T-cell development and receptor diversity during aging. Curr Opin Immunol 17:468–475
Cicin-Sain L, I Messaoudi, B Park, N Currier, S Planer, M Fischer, S Tackitt, D Nikolich-Zugich, A Legasse, MK Axthelm, LJ Picker, M Mori, J Nikolich-Zugich (2007) Dramatic increase in naive T-cell turnover is linked to loss of naive T cells from old primates. Proc Natl Acad Sci U S A 104:19960–19965
Kotzin BL, VL Barr, E. Palmer (1985) A large deletion within the T-cell receptor beta-chain gene complex in New Zealand white mice. Science (New York, N.Y) 229:167–171
Nanda NK, R Apple, E Sercarz (1991) Limitations in plasticity of the T-cell receptor repertoire. Proc Natl Acad Sci U S A 88:9503–9507
Gilfillan S, A Dierich, M Lemeur, C Benoist, D Mathis (1993) Mice lacking TdT: mature animals with an immature lymphocyte repertoire. Science (New York, N.Y) 261:1175–1178
Kikly K, G Dennert (1992) Evidence for a role for T-cell receptors (TCR) in the effector phase of acute bone marrow graft rejection. TCR V beta 5 transgenic mice lack effector cells able to cause graft rejection. J Immunol 149:3489–3494
Perkins DL, YS Wang, D Fruman, JG Seidman, IJ Rimm (1991) Immunodominance is altered in T-cell receptor (beta-chain) transgenic mice without the generation of a hole in the repertoire. J Immunol 146:2960–2964
Noguchi M, H Yi, HM Rosenblatt, AH Filipovich, S Adelstein, WS Modi, OW McBride, W J Leonard (1993) Interleukin-2 receptor gamma chain mutation results in X-linked severe combined immunodeficiency in humans. Cell 73:147–157
Stephan V, V Wahn, F Le Deist, U Dirksen, B Broker, I Muller-Fleckenstein, G Horneff, H Schroten, A Fischer, G de Saint Basile (1996) Atypical X-linked severe combined immunodeficiency due to possible spontaneous reversion of the genetic defect in T cells. N Engl J Med 335:1563–1567
Bousso P, V Wahn, I Douagi, G Horneff, C Pannetier, F Le Deist, F Zepp, T Niehues, P Kourilsky, A Fischer, G de Saint Basile (2000) Diversity, functionality, and stability of the T-cell repertoire derived in vivo from a single human T-cell precursor. Proc Natl Acad Sci U S A 97:274–278
Meyer-Olson D, NH Shoukry, KW Brady, H Kim, DP Olson, K Hartman, AK Shintani, CM Walker, SA Kalams (2004) Limited T-cell receptor diversity of HCV-specific T-cell responses is associated with CTL escape. J Exp Med 200:307–319
Ferguson FG, A Wikby, P Maxson, J Olsson, B Johansson (1995) Immune parameters in a longitudinal study of a very old population of Swedish people: a comparison between survivors and nonsurvivors. J Gerontol 50:B378–B382
Wikby A, P Maxson, J Olsson, B Johansson, FG Ferguson (1998) Changes in CD8 and CD4 lymphocyte subsets, T-cell proliferation responses and non-survival in the very old: the Swedish longitudinal OCTO-immune study. Mech Ageing Dev 102:187–198
Khan N, A Hislop, N Gudgeon, M Cobbold, R Khanna, L Nayak, A B Rickinson, PA Moss (2004) Herpesvirus-specific CD8 T-cell immunity in old age: cytomegalovirus impairs the response to a coresident EBV infection. J Immunol 173:7481–7489
Goronzy JJ, JW Fulbright, CS Crowson, GA Poland, W. M. O’Fallon, and CM Weyand. (2001) Value of immunological markers in predicting responsiveness to influenza vaccination in elderly individuals. J Virol 75:12182–12187
Trzonkowski P, J Mysliwska, E Szmit, J Wieckiewicz, K Lukaszuk, LB Brydak, M Machala, A Mysliwski (2003) Association between cytomegalovirus infection, enhanced proinflammatory response and low level of anti-hemagglutinins during the anti-influenza vaccination—an impact of immunosenescence. Vaccine 21:3826–3836
Strindhall J, BO Nilsson, S Lofgren, J Ernerudh, G Pawelec, B Johansson, A Wikby (2007) No immune risk profile among individuals who reach 100 years of age: findings from the Swedish NONA immune longitudinal study. Exp Gerontol 42:753–761
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2009 Springer Science+Business Media B.V.
About this chapter
Cite this chapter
Lamar, D.L., Weyand, C.M., Goronzy, J.J. (2009). Age, T-cell Homeostasis, and T-cell Diversity in Humans. In: Fulop, T., Franceschi, C., Hirokawa, K., Pawelec, G. (eds) Handbook on Immunosenescence. Springer, Dordrecht. https://doi.org/10.1007/978-1-4020-9063-9_9
Download citation
DOI: https://doi.org/10.1007/978-1-4020-9063-9_9
Publisher Name: Springer, Dordrecht
Print ISBN: 978-1-4020-9062-2
Online ISBN: 978-1-4020-9063-9
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)