Journal of Clinical Immunology

, Volume 20, Issue 4, pp 250–256 | Cite as

Thymic Involution in Aging

  • Richard Aspinall
  • Deborah Andrew


The size of the na¨ıve T-cell pool is governed by output from the thymus and not by replication. This pool contributes cells to the activated/memory T-cell pool whose size can be increased through cell multiplication; both pools together constitute the peripheral T-cell pool. Aging is associated with involution of the thymus leading to a reduction in its contribution to the na¨ıve T-cell pool; however, despite this diminished thymic output, there is no significant decline in the total number of T cells in the peripheral T-cell pool. There are, however, considerable shifts in the ratios of both pools of cells, with an increase in the number of activated/memory T cells and the accumulation in older individuals of cells that fail to respond to stimuli as efficiently as T cells from younger individuals. Aging is also associated with a greater susceptibility to some infections and some cancers. An understanding of the causal mechanism of thymic involution could lead to the design of a rational therapy to reverse the loss of thymic tissue, renew thymic function, increase thymic output, and potentially improve immune function in aged individuals.

Thymus atrophy aging involution transgenic mice IL-7 


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  1. 1.
    Brock DB, Guralnik JM, Brody JA: Demography and epidemiology of aging in the United States In Handbook of the Biology of Aging, 3rd ed., EL Schneider and JW Rowe (eds). (New York, Academic Press, 1990), pp. 3-23.Google Scholar
  2. 2.
    Scollay RG, Butcher EC, Weissman IL: Thymus cell migration. Quantitative aspects of cellular traffic from the thymus to the periphery in mice. Eur J Immunol 10:210-218, 1980.Google Scholar
  3. 3.
    Mackall CL, Fleisher TA, Brown MR, Andrich MP, Chen CC, Feuerstein IM, Horowitz ME, Magrath IT, Shad AT, Steinberg SM, et al: Age, thymopoiesis, and CD4+ T-lymphocyte regeneration after intensive chemotherapy. N Engl J Med 332:143-149, 1995.Google Scholar
  4. 4.
    Douek DC, McFarland RD, Keiser PH, Gage EA, Massey JM, Haynes BF, Polis MA, Haase AT, Feinberg MB, Sullivan JL, Jamieson BD, Zack JA, Picker LJ, Koup RA: Changes in thymic function with age and during the treatment of HIV infection. Nature 396:690-695, 1998.Google Scholar
  5. 5.
    Kampinga J, Groen H, Klatter FA, Pater JM, van Petersen AS, Roser B, Nieuwenhuis P, Aspinall R: Post-thymic T-cell development in the rat. Thymus 24:173-200, 1997.Google Scholar
  6. 6.
    Hulstaert F, Hannet I, Deneys V, Munhyeshuli V, Reichert T, De Bruyere M, Strauss K: Age-related changes in human blood lymphocyte subpopulations. II. Varying kinetics of percentage and absolute count measurements. Clin Immunol Immunopathol 70:152-158, 1994.Google Scholar
  7. 7.
    Utsuyama M, Hirokawa K: Age-related changes of splenic T cells in mice—A flow cytometric analysis. Mech Ageing Dev 40:89-102, 1987.Google Scholar
  8. 8.
    Perillo NL, Walford RL, Newman MA, Effros RB: Human T lymphocytes possess a limited in vitro life span. Exp Gerontol 24:177-187, 1989.Google Scholar
  9. 9.
    Pawelec G, Rehbein A, Haehnel K, Merl A, Adibzadeh M: Human T-cell clones in long-term culture as a model of immunosenescence. Immunol Rev 160:31-42, 1997.Google Scholar
  10. 10.
    Effros RB, Pawelec G: Replicative senescence of T cells: Does the Hayflick limit lead to immune exhaustion? Immunology Today 18:450-454, 1997.Google Scholar
  11. 11.
    Murasko DM, Weiner P, Kaye D: Decline in mitogen induced proliferation of lymphocytes with increasing age. Decline in mitogen induced proliferation of lymphocytes with increasing age. Clin Exp Immunol 70:440-448, 1987.Google Scholar
  12. 12.
    Hobbs MV, Weigle WO, Noonan DJ, Torbett BE, McEvilly RJ, Koch RJ, Cardenas GJ, Ernst DN: Patterns of cytokine gene expression by CD4— T cells from young and old mice. J Immunol 150 150:3602-3614, 1993.Google Scholar
  13. 13.
    Jackola DR, Ruger JK, Miller RA: Age-associated changes in human T cell phenotype and function. Aging Milano 6:25-34, 1994.Google Scholar
  14. 14.
    Engwerda CR, Handwerger BS, Fox BS: Aged T cells are hyporesponsive to costimulation mediated by CD28. J Immunol 152:3740-3747, 1994.Google Scholar
  15. 15.
    Nociari MM, Telford W, Russo C: Postthymic development of CD282CD81 T cell subset: Age-associated expansion and shift from memory to naive phenotype. J Immunol 162:3327-3335, 1999.Google Scholar
  16. 16.
    Quadri RA, Plastre O, Phelouzat MA, Arbogast A, Proust JJ: Age-related tyrosine-specific protein phosphorylation defect in human T lymphocytes activated through CD3, CD4, CD8 or the IL-2 receptor. Mech Ageing Dev 88:125-138, 1996.Google Scholar
  17. 17.
    Whisler RL, Newhouse YG, Bagenstose SE: Age-related reductions in the activation of mitogen-activated protein kinases p44mapk/ERK1 and p42mapk/ERK2 in human T cells stimulated via ligation of the T cell receptor complex. Cell Immunol 168:201-210, 1996.Google Scholar
  18. 18.
    Quadri RA, Arbogast A, Phelouzat MA, Boutet S, Plastre O, Proust JJ: Age-associated decline in cdk1 activity delays cell cycle progression of human T lymphocytes. J Immunol 161:5203-5209, 1998.Google Scholar
  19. 19.
    Engwerda CR, Fox BS, Handwerger BS: Cytokine production by T lymphocytes from young and aged mice. J Immunol 156:3621-3630, 1996.Google Scholar
  20. 20.
    Hobbs MV, Ernst DN, Torbett BE, Glasebrook AL, Rehse MA, McQuitty DN, Thoman ML, Bottomly K, Rothermel AL, Noonan DJ, et al: Cell proliferation and cytokine production by CD4+ cells from old mice. J Cell Biochem 46:312-320, 1991.Google Scholar
  21. 21.
    Steinmann GG: Changes in the human thymus during aging. Curr Top Pathol 75:43-88, 1986.Google Scholar
  22. 22.
    Kendall MD, Johnson HR, Singh J: The weight of the human thymus gland at necropsy. J Anat 131:483-497, 1980.Google Scholar
  23. 23.
    Bertho JM, Demarquay C, Moulian N, Van De Meeren A, Berrih-Akhnin S, Gourmelon P: Phenotypic and immunohistological analyses of the human adult thymus: Evidence for an active thymus during adult life. Cell Immunol 179:30-40, 1997.Google Scholar
  24. 24.
    Aspinall R: Age-associated thymic atrophy in the mouse is due to a deficiency affecting rearrangement of the TCR during intrathymic T cell development. J Immunol 158:3037-3045, 1997.Google Scholar
  25. 25.
    Wu L, Scollay R, Egerton M, Pearse M, Spangrude GJ, Shortman K: CD4 expressed on earliest T-lineage precursor cells in the adult murine thymus. Nature 349:71-74, 1991.Google Scholar
  26. 26.
    Rahemtulla A, Fung Leung WP, Schilham MW, Kundig TM, Sambhara SR, Narendran A, Arabian A, Wakeham A, Paige CJ, Zinkernagel RM, et al: Normal development and function of CD8+ cells but markedly decreased helper cell activity in mice lacking CD4. Nature 353:180-184, 1991.Google Scholar
  27. 27.
    Dudley EC, Petrie HT, Shah LM, Owen MJ, Hayday AC: T cell receptor beta chain gene rearrangement and selection during thymocyte development in adult mice. Immunity 1:83-93, 1994.Google Scholar
  28. 28.
    Su DM, Wang J, Lin Q, Cooper MD, Watanabe T: Interferons alpha/beta inhibit IL-7-induced proliferation of CD4-CD8-CD-CD44+CD25+ thymocytes, but do not inhibit that of CD4-CD8-CD3-CD44-CD25- thymocytes. Immunology 90:543-549, 1997.Google Scholar
  29. 29.
    Godfrey DI, Kennedy J, Suda T, Zlotnik A: A developmental pathway involving four phenotypically and functionally distinct subsets of CD3-CD4-CD8- triple-negative adult mouse thymocytes defined by CD44 and CD25 expression. J Immunol 150: 4244-4252, 1993.Google Scholar
  30. 30.
    Godfrey DI, Kennedy J, Mombaerts P, Tonegawa S, Zlotnik A: Onset of TCR-beta gene rearrangement and role of TCR-beta expression during CD3-CD4-CD8- thymocyte differentiation. J Immunol 152:4783-4792, 1994.Google Scholar
  31. 31.
    Moore TA, Zlotnik A: T-cell lineage commitment and cytokine responses of thymic progenitors. Blood 86:1850-1860, 1995.Google Scholar
  32. 32.
    Alam SM, Travers PJ, Wung JL, Nasholds W, Redpath S, Jameson SC, Gascoigne NR: T-cell-receptor affinity and thymocyte positive selection. Nature 381:616-620, 1996.Google Scholar
  33. 33.
    Brandle D, Muller C, Rulicke T, Hengartner H, Pircher H: Engagement of the T-cell receptor during positive selection in the thymus down-regulates RAG-1 expression. Proc Natl Acad Sci USA 89:9529-9533, 1992.Google Scholar
  34. 34.
    Petrie HT, Livak F, Schatz DG, Strasser A, Crispe IN, Shortman K: Multiple rearrangements in T cell receptor alpha chain genes maximize the production of useful thymocytes. J Exp Med 178:615-622, 1993.Google Scholar
  35. 35.
    Jameson SC, Hogquist KA, Bevan MJ: Positive selection of thymocytes. Annu Rev Immunol 13:93-126, 1995.Google Scholar
  36. 36.
    Penit C, Vasseur F: Expansion of mature thymocyte subsets before emigration to the periphery. J Immunol 159:4848-4856, 1997.Google Scholar
  37. 37.
    Mamalaki C, Elliot J, Norton T, Yannoutsos N, Townsend AR, Chandler P, Simpson E, Kioussis D: Positive and negative selection in transgenic mice expressing a T-cell receptor specific for influenza nucleoprotein and endogenous superantigen. Dev Immunol 3:159-174, 1993.Google Scholar
  38. 38.
    Lacorazza HD, Patino JAG, Weksler ME, Radu D, Nikolic-Zugic J: Failure of rearranged TCR transgenes to prevent age-associated thymic involution. J Immunol 163:4262-4268, 1999.Google Scholar
  39. 39.
    Tyan ML: Age-related decrease in mouse T cell progenitors. J Immunol 118:846-851, 1977.Google Scholar
  40. 40.
    Tyan ML: Impaired thymic regeneration in lethally irradiated mice given bone marrow from aged donors. Proc Soc Exp Biol Med 152:33-35, 1976.Google Scholar
  41. 41.
    Mackall CL, Punt JA, Morgan P, Farr AG, Gress RE: Thymic function in young/old chimeras: Substantial thymic T cell regenerative capacity despite irreversible age-associated thymic involution. Eur J Immunol 28:1886-1893, 1998.Google Scholar
  42. 42.
    Doria G, Mancini C, Utsuyama M, Frasca D, Hirokawa K: Aging of the recipients but not of the bone marrow donors enhances autoimmunity in syngeneic radiation chimeras. Mech Ageing Dev 95:131-142, 1997.Google Scholar
  43. 43.
    Yu S, Abel L, Globerson A: Thymocyte progenitors and T cell development in aging. Mech Ageing Dev 94:103-111, 1997.Google Scholar
  44. 44.
    Sharp A, Kukulansky T, Globerson A: In vitro analysis of age-related changes in the developmental potential of bone marrow thymocyte progenitors. Eur J Immunol 20:2541-2546, 1990.Google Scholar
  45. 45.
    Mackall CL, Gress RE: Thymic aging and T-cell regeneration. Immunol Rev 160:91-102, 1997.Google Scholar
  46. 46.
    Penit C, Lucas B, Vasseur F, Rieker T, Boyd RL: Thymic medulla epithelial cells acquire specific markers by post-mitotic maturation. Dev Immunol 5:25-36, 1996.Google Scholar
  47. 47.
    Shores EW, van Ewijk W, Singer A: Maturation of medullary thymic epithelium requires thymocytes expressing fully assembled CD3-TCR complexes. Int Immunol 6:1393-1402, 1994.Google Scholar
  48. 48.
    Hartwig M, Steinmann G: On a causal mechanism of chronic thymic involution in man. Mech Ageing Dev 75:151-156, 1994.Google Scholar
  49. 49.
    Haynes BF, Shimizu K, Eisenbarth GS: Identification of human and rodent thymic epithelium using tetanus toxin and monoclonal antibody A2B5. J Clin Invest 71:9-14, 1983.Google Scholar
  50. 50.
    Klug DB, Carter C, Crouch E, Roop D, Conti CJ, Richie ER: Interdependence of cortical thymic epithelial cell differentiation and T-lineage commitment. Proc Natl Acad Sci USA 95:11822-11827, 1998.Google Scholar
  51. 51.
    Farr AG, Rudensky A: Medullary thymic epithelium: a mosaic of epithelial “self”? J Exp Med 188:1-4, 1998.Google Scholar
  52. 52.
    Porcellini S, Panigada M, Grassi F: Molecular and cellular aspects of induced thymus development in recombinase-deficient mice. Eur J Immunol 29:2476-2483, 1999.Google Scholar
  53. 53.
    Anderson KL, Moore NC, McLoughlin DE, Jenkinson EJ, Owen JJ: Studies on thymic epithelial cells in vitro. Dev Comp Immunol 22:367-377, 1998.Google Scholar
  54. 54.
    Wynford Thomas D: Proliferative life span checkpoints: Cell-type specificity and influence on tumour biology. Eur J Cancer 33:716-726, 1997.Google Scholar
  55. 55.
    Dimri GP, Lee X, Basile G, Acosta M, Scott G, Roskelley C, Medrano EE, Linskens M, Rubelj I, Pereira Smith O, et al: A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci USA 92:9363-9367, 1995.Google Scholar
  56. 56.
    Smith JR, Pereira Smith OM: Replicative senescence: Implications for in vivo aging and tumor suppression. Science 273:63-67, 1996.Google Scholar
  57. 57.
    Farr AG, Sidman CL: Reduced expression of Ia antigens by thymic epithelial cells of aged mice. J Immunol 133:98-103, 1984.Google Scholar
  58. 58.
    Bhatia SK, Tygrett LT, Grabstein KH, Waldschmidt TJ: The effect of in vivo IL-7 deprivation on T cell maturation. J Exp Med 181:1399-1409, 1995.Google Scholar
  59. 59.
    Crompton T, Outram SV, Buckland J, Owen MJ: A transgenic T cell receptor restores thymocyte differentiation in interleukin-7 receptor α chain deficient mice. Eur J Immunol 27:100-104, 1997.Google Scholar
  60. 60.
    Muegge K, Vila MP, Durum SK: Interleukin-7: A cofactor for V(D)J rearrangement of the T cell receptor beta gene. Science 261:93-95, 1993.Google Scholar
  61. 61.
    Tsuda S, Rieke S, Hashimoto Y, Nakauchi H, Takahama Y: IL-7 supports D-J but not V-DJ rearrangement of TCR-beta gene in fetal liver progenitor cells. J Immunol 156:3233-3242, 1996.Google Scholar
  62. 62.
    Oosterwegel MA, Haks MC, Jeffry U, Murray R, Kruisbeek AM: Induction of TCR gene rearrangements in uncommitted stem cells by a subset of IL-7 producing, MHC class-II-expressing thymic stromal cells. Immunity 6:351-360, 1997.Google Scholar
  63. 63.
    Kelley KW, Brief S, Westly HJ, Novakofski J, Bechtel PJ, Simon J, Walker EB: GH3 pituitary adenoma cells can reverse thymic aging in rats. Proc Natl Acad Sci USA 83:5663-5667, 1986.Google Scholar
  64. 64.
    Li YM, Brunke DL, Dantzer R, Kelley KW: Pituitary epithelial cell implants reverse the accumulation of CD42CD82 lymphocytes in thymus glands of aged rats. Endocrinology 130:2703-2709, 1992.Google Scholar
  65. 65.
    Binz K, Joller P, Froesch P, Binz H, Zapf J, Froesch ER: Repopulation of the atrophied thymus in diabetic rats by insulinlike growth factor I. Proc Natl Acad Sci USA 87:3690-3694, 1990.Google Scholar
  66. 66.
    Marchetti B, Guarcello V, Morale MC, Bartoloni G, Raiti F, Palumbo G, Jr, Farinella Z, Cordaro S, Scapagnini U: Luteinizing hormone-releasing hormone (LHRH) agonist restoration of ageassociated decline of thymus weight, thymic LHRH receptors, and thymocyte proliferative capacity. Endocrinology 125:1037-1045, 1989.Google Scholar
  67. 67.
    Kendall MD, Fitzpatrick FT, Greenstein BD, Khoylou F, Safieh B, Hamblin A: Reversal of ageing changes in the thymus of rats by chemical or surgical castration. Cell Tissue Res 261:555-564, 1990.Google Scholar
  68. 68.
    Fitzpatrick FT, Kendall MD, Wheeler MJ, Adcock IM, Greenstein BD: Reappearance of thymus of ageing rats after orchidectomy. J Endocrinol 106:R17-9, 1985.Google Scholar
  69. 69.
    Aspinall R, Andrew D: Thymic atrophy in the mouse is a soluble problem of the thymic microenvironment. Vaccine 18:1629-1637, 2000.Google Scholar
  70. 70.
    Bui T, Faltynek C, Ho RJ: Differential disposition of soluble and liposome-formulated human recombinant interleukin-7: Effects on blood lymphocyte population in guinea pigs. Pharm Res 11:633-641, 1994.Google Scholar
  71. 71.
    Tanchot C, Rocha B: Peripheral selection of T cell repertoires: The role of continuous thymus output. J Exp Med 186:1099-1106, 1997.Google Scholar
  72. 72.
    Berzins SP, Boyd RL, Miller JF: The role of the thymus and recent thymic migrants in the maintenance of the adult peripheral lymphocyte pool. J Exp Med 187:1839-1848, 1998.Google Scholar
  73. 73.
    Berzins SP, Godfrey DI, Miller JF, Boyd RL: A central role for thymic emigrants in peripheral T cell homeostasis. Proc Natl Acad Sci USA 96:9787-9791, 1999.Google Scholar
  74. 74.
    Thoman ML: Effects of the aged microenvironment on CD4+ T cell maturation. Mech Ageing Dev 96:75-88, 1997Google Scholar

Copyright information

© Plenum Publishing Corporation 2000

Authors and Affiliations

  • Richard Aspinall
    • 1
  • Deborah Andrew
    • 1
  1. 1.Department of ImmunologyICSTM at Chelsea and Westminster HospitalLondonEngland

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