Skip to main content
SpringerLink
Log in

Development and Reconstitution of T-Lymphoid Immunity

  • Chapter
Retroviral Immunology

Part of the book series: Infectious Disease ((ID))

  • 150 Accesses

Abstract

Remarkable progress has been made in our understanding of the mechanisms by which the immune system responds to challenge by invading pathogens. Driven by urgent clinical problems, including the pandemic caused by human immunodeficiency virus type 1 (HIV-1) (1,2), these basic advances are starting to yield rewards in the treatment of human disease. Despite these gains, many fundamental questions remain unanswered, including many related to the factors that govern reconstitution of the immune system following its destruction in the setting of human disease.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. McCune JM. HIV-1: the infective process in vivo. Cell 1991; 64: 351–63.

    Article  PubMed  CAS  Google Scholar 

  2. Pantaleo G, Graziosi C, Fauci AS. The immunopathogenesis of human immunodeficiency virus infection. N Engl J Med 1993; 328: 327–35.

    Article  PubMed  CAS  Google Scholar 

  3. Palella FJ, Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. N Engl J Med 1998; 338: 853–60.

    Article  PubMed  Google Scholar 

  4. Autran B, Carcelain G, Li TS, Blanc C, Mathez D, Tubiana R, et al. Positive effects of cornbined antiretroviral therapy on CD4+ T cell homeostasis and function in advanced HIV disease. Science 1997; 277: 112–6.

    Article  PubMed  CAS  Google Scholar 

  5. Gorochov G, Neumann AU, Kereveur A, Parizot C, Li T, Katlama C, et al. Perturbation of CD4+ and CD8+ T-cell repertoires during progression to AIDS and regulation of the CD4+ repertoire during antiviral therapy. Nat Med 1998; 4: 215–21.

    Article  PubMed  CAS  Google Scholar 

  6. Li TS, Tubiana R, Katlama C, Calvez V, Ait Mohand H, Autran B. Long-lasting recovery in CD4 T-cell function and viral-load reduction after highly active antiretroviral therapy in advanced HIV-1 disease. Lancet 1998; 351: 1682–6.

    Article  PubMed  CAS  Google Scholar 

  7. Komanduri KV, Viswanathan MN, Wieder ED, Schmidt DK, Bredt BM, Jacobson MA, McCune JM. Restoration of cytomegalovirus-specific CD4+ T-lymphocyte responses after ganciclovir and highly active antiretroviral therapy in individuals infected with HIV-1. Nat Med 1998; 4: 953–6.

    Article  PubMed  CAS  Google Scholar 

  8. Lederman MM, Connick E, Landay A, Kuritzkes DR, Spritzler J, St. Clair M, et al. Immunologic responses associated with 12 weeks of combination antiretroviral therapy consisting of zidovudine, lamivudine, and ritonavir: results of AIDS Clinical Trials Group Protocol 315. J Infect Dis 1998; 178: 70–9.

    Article  PubMed  CAS  Google Scholar 

  9. Connors M, Kovacs JA, Krevat S, Gea-Banacloche JC, Sneller MC, Flanigan M, et al. HIV infection induces changes in CD4+ T-cell phenotype and depletions within the CD4+ T-cell repertoire that are not immediately restored by antiviral or immune-based therapies. Nat Med 1997; 3: 533–40.

    Article  PubMed  CAS  Google Scholar 

  10. Jacobson MA, Zegans M, Pavan PR, O’Donnell JJ, Sattler F, Rao N, et al. Cytomegalovirus retinitis after initiation of highly active antiretroviral therapy. Lancet 1997; 349: 1443–5.

    Article  PubMed  CAS  Google Scholar 

  11. Miller JFAP. Immunological function of the thymus. Lancet 1961; ii:748–9.

    Google Scholar 

  12. Miller JFAP. Immunological significance of the thymus of the adult mouse. Nature 1962; 195: 1318–9.

    Article  Google Scholar 

  13. Gowans JL, McGregor DD, Cowen DM, Ford CE. Initiation of immune responses by small lymphocytes. Nature 1962; 196: 651–5.

    Article  PubMed  CAS  Google Scholar 

  14. Miller JF, Mitchell GF. The thymus and the precursors of antigen reactive cells. Nature 1967; 216: 659–63.

    Article  PubMed  CAS  Google Scholar 

  15. Brummendorf TH, Dragowska W, Zijlmans J, Thornbury G, Lansdorp PM. Asymmetric cell divisions sustain long-term hematopoiesis from single-sorted human fetal liver cells. J Exp Med 1998; 188: 1117–24.

    Article  PubMed  CAS  Google Scholar 

  16. Morrison SJ, Wright DE, Cheshier SH, Weissman IL. Hematopoietic stem cells: challenges to expectations. Curr Opin Immunol 1997; 9: 216–21.

    Article  PubMed  CAS  Google Scholar 

  17. Haynes BF, Heinly CS. Early human T cell development: analysis of the human thymus at the time of initial entry of hematopoietic stem cells into the fetal thymic microenvironment. J Exp Med 1995; 181: 1445–58.

    Article  PubMed  CAS  Google Scholar 

  18. Gale RP. Development of the immune system in the human fetal liver. Thymus 1987; 10: 45–52.

    PubMed  CAS  Google Scholar 

  19. Schmitt C, Ktorza S, Sarun S, Verpilleux MP, Blanc C, Deugnier MA, et al. CD34-positive early stages of human T-cell differentiation. Leuk Lymph 1995; 17: 43–50.

    Article  CAS  Google Scholar 

  20. Spits H. Early stages in human and mouse T-cell development. Curr Opin Immunol 1994; 6: 212–21.

    Article  PubMed  CAS  Google Scholar 

  21. Scollay R, Smith J, Stauffer V. Dynamics of early T cells: prothymocyte migration and proliferation in the adult mouse thymus. Immunol Rev 1986; 91: 129–57.

    Article  PubMed  CAS  Google Scholar 

  22. Baum CM, Weissman IL, Tsukamoto AS, Buckle AM, Peault B. Isolation of a candidate human hematopoietic stem cell population. Proc Natl Acad Sci USA 1992; 89: 2804–8.

    Article  PubMed  CAS  Google Scholar 

  23. Galy A, Verma S, Bârcena A, Spits H. Precursors of CD3+ CD4+ CD8+ cells in the human thymus are defined by expression of CD34. Delineation of early events in human thymic development. J Exp Med 1993; 178: 391–401.

    Article  PubMed  CAS  Google Scholar 

  24. Res P, Martinez-Caceres E, Cristina Jaleco A, Staal F, Noteboom E, Weijer K, Spits H. CD34+ CD38dim cells in the human thymus can differentiate into T, natural killer, and dendritic cells but are distinct from pluripotent stem cells. Blood 1996; 87: 5196–206.

    PubMed  CAS  Google Scholar 

  25. Barcena A, Galy AH, Punnonen J, Muench MO, Schols D, Roncarolo MG, et al. Lymphoid and myeloid differentiation of fetal liver CD34+-lineage cells in human thymic organ culture. J Exp Med 1994; 180: 123–32.

    Article  PubMed  CAS  Google Scholar 

  26. Blom B, Res P, Noteboom E, Weijer K, Spits H. Prethymic CD34+ progenitors capable of developing into T cells are not committed to the T cell lineage. J Immunol 1997; 158: 3571–7.

    PubMed  CAS  Google Scholar 

  27. Ramiro AR, Trigueros C, Marquez C, San Millan JL, Toribio ML. Regulation of pre-T cell receptor (pT alpha-TCR beta) gene expression during human thymic development. J Exp Med 1996; 184: 519–30.

    Article  PubMed  CAS  Google Scholar 

  28. Fehling HJ, von Boehmer H. Early alpha beta T cell development in the thymus of normal and genetically altered mice. Curr Opin Immunol 1997; 9: 263–75.

    Article  PubMed  CAS  Google Scholar 

  29. Kong F, Chen CH, Cooper MD. Thymic function can be accurately monitored by the level of recent T cell emigrants in the circulation. Immunity 1998; 8: 97–104.

    Article  PubMed  CAS  Google Scholar 

  30. McCune JM. Development and applications of the SCID-hu mouse model. Semin Immunol 1996; 8: 187–96.

    Article  PubMed  CAS  Google Scholar 

  31. Weissman IL. Thymus cell maturation. Studies on the origin of cortisone-resistant thymic lymphocytes. J Exp Med 1973; 137: 504–10.

    Article  PubMed  CAS  Google Scholar 

  32. Fathman CG, Small M, Herzenberg LA, Weissman IL. Thymus cell maturation. II. Differentiation of three “mature” subclasses in vivo. Cell Immunol 1975; 15: 109–28.

    Article  PubMed  CAS  Google Scholar 

  33. Dunon D, Imhof BA. Mechanisms of thymus homing. Blood 1993; 81: 1–8.

    PubMed  CAS  Google Scholar 

  34. Wu L, Li C, Shortman K. Thymic dendritic cell precursors: relationship to the T lymphocyte lineage and phenotype of the dendritic cell progeny. J Exp Med 1996; 184: 903–11.

    Article  PubMed  CAS  Google Scholar 

  35. Galy AHM, Cen D, Travis M, Chen S, Chen BR. Delination of T-progenitor activity within the CD34+ compartment of adult bone marrow. Blood 1995; 85: 2770–78.

    PubMed  CAS  Google Scholar 

  36. Galy A, Travis M, Cen D, Chen B. Human T, B, natural killer, and dendritic cells arise from a common bone marrow progenitor cell subset. Immunity 1995; 3: 459–73.

    Article  PubMed  CAS  Google Scholar 

  37. Miller JS, Verfaillie C, McGlave P. The generation of human natural killer cells from CD34+/DR- primitive progenitors in long-term bone marrow culture. Blood 1992; 69: 2182–7.

    Google Scholar 

  38. Sanchez MJ, Muench MO, Roncarolo MG, Lanier LL, Phillips JH. Identification of a common T/natural killer cell progenitor in human fetal thymus. J Exp Med 1994; 180: 569–76.

    Article  PubMed  CAS  Google Scholar 

  39. Zúniga-Pflücker JC, Lenardo MJ. Regulation of thymocyte development from immature progenitors. Curr Opin Immunol 1996; 8: 215–24.

    Article  PubMed  Google Scholar 

  40. 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 1991; 349: 71–4.

    Article  PubMed  CAS  Google Scholar 

  41. Godfrey DI, Zlotnik A, Suda T. Phenotypic and functional characterization of c-kit expression during intrathymic T cell development. J Immunol 1992; 149: 2281–5.

    PubMed  CAS  Google Scholar 

  42. Godfrey DI, Kennedy J, Suda T, Zlotnik A. A developmental pathway involving four phenotypically and functionally distinct sets of CD3- CD4- CD8- triple-negative adult mouse thymocytes defined by CD44 and CD25 expression. J Immunol 1993; 150: 4244–52.

    PubMed  CAS  Google Scholar 

  43. 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 1994; 152: 4783–92.

    PubMed  CAS  Google Scholar 

  44. Wurch A, Biro J, Potocnik A, Falk I, Mossmann H, Eichmann K. Requirement of CD3 complex-associated signaling functions for expression of rearranged T cell recepter beta VDJ genes in early thymic development. J Exp Med 1998; 188: 1669–78.

    Article  PubMed  CAS  Google Scholar 

  45. Saint-Ruf C, Ungewiss K, Groettrup M, Bruno L, Fehling HJ, von Boehmer H. Analysis and expression of a cloned pre-T cell receptor gene. Science 1994; 266: 1208–12.

    Article  PubMed  CAS  Google Scholar 

  46. Owen MJ, Venkitaraman AR. Signalling in lymphocyte development. Curr Opin Immunol 1996; 8: 191–8.

    Article  PubMed  CAS  Google Scholar 

  47. Trigueros C, Ramiro AR, Carrasco YR, de Yebenes VG, Albar JP, Tiribio ML. Identification of a late stage of small noncycling pT-alpha negative T cells as immediate precursors of T cell receptor alpha/beta thymocytes. J Exp Med 1998; 188: 1401–12.

    Article  PubMed  CAS  Google Scholar 

  48. Kraft DL, Weissman IL, Waller EK. Differentiation of CD3–4–8– human fetal thymocytes in vivo: characterization of a CD3–4+ 8– intermediate. J Exp Med 1993; 178: 265 – 77.

    Article  PubMed  CAS  Google Scholar 

  49. Guidos CJ. Positive selection of CD4+ and CD8+ T cells. Curr Opin Immunol 1996; 8: 225–32.

    Article  PubMed  CAS  Google Scholar 

  50. Vanhecke D, Leclercq G, Plum J, Vandekerckhove B. Characterization of distinct stages during the differentiation of human CD69+ CD3+ thymocytes and identification of thymic emigrants. J Immunol 1995; 155: 1862–72.

    PubMed  CAS  Google Scholar 

  51. Vanhecke D, Verhasselt B, Debacker V, Leclercq G, Plum J, Vandekerckhove B. Differentiation to T helper cells in the thymus. Gradual acquisition of T helper cell function by CD3+ CD4+ cells. J Immunol 1995; 155: 4711–8.

    PubMed  CAS  Google Scholar 

  52. Res P, Blom B, Hori T, Weijer K, Spits H. Downregulation of CD1 marks acquisition of functional maturation of human thymocytes and defines a control point in late stages of human T cell development. Journal of Exp Med 1997; 185: 141–51.

    Article  CAS  Google Scholar 

  53. Benoist C, Mathis D. Positive selection of T cells: fastidious or promiscuous? Curr Opin Immunol 1997; 9: 245–9.

    Article  PubMed  CAS  Google Scholar 

  54. Marrack P, Kappler J. Positive selection of thymocytes bearing alpha beta T cell receptors. Curr Opin Immunol 1997; 9: 250–5.

    Article  PubMed  CAS  Google Scholar 

  55. Lucas B, Germain RN. T-cell repertoire: political correctness in the immune system. Curr Biol 1996; 6: 783–7.

    Article  PubMed  CAS  Google Scholar 

  56. Ashton-Rickardt PG, Bandeira A, Delaney JR, Van Kaer L, Pircher HP, Zinkernagel RM, Tonegawa S. Evidence for a differential avidity model of T cell selection in the thymus. Cell 1994; 76: 651–63.

    Article  PubMed  CAS  Google Scholar 

  57. Sebzda E, Wallace VA, Mayer J, Yeung RS, Mak TW, Ohashi PS. Positive and negative thymocyte selection induced by different concentrations of a single peptide. Science 1994; 263: 1615–8.

    Article  PubMed  CAS  Google Scholar 

  58. Hogquist KA, Jameson CS, Heath WR, Howard JL, Bevan MJ, Carbone FR. T cell receptor antagonist peptides induce positive selection. Cell 1994; 76: 17–27.

    Article  PubMed  CAS  Google Scholar 

  59. Hogquist KA, Tomlinson AJ, Kieper WC, McGargill MA, Hart MC, Naylor S, Jameson SC. Identification of a naturally occurring ligand for thymic positive selection. Immunity 1997; 6: 389–99.

    Article  PubMed  CAS  Google Scholar 

  60. Pawlowski TJ, Singleton MD, Loh DY, Berg R, Staerz UD. Permissive recognition during positive selection. Eur J Immunol 1996; 26: 851–7.

    Article  PubMed  CAS  Google Scholar 

  61. Nakano N, Rooke R, Benoist C, Mathis D. Positive selection of T cells induced by viral delivery of neopeptides to the thymus. Science 1997; 275: 678–83.

    Article  PubMed  CAS  Google Scholar 

  62. Ding YH, Smith KJ, Garboczi DN, Utz U, Biddison WE, Wiley DC. Two human T cell receptors bind in a similar diagonal mode to the HLA-A2/Tax peptide complex using different TCR amino acids. Immunity 1998; 8: 403–11.

    Article  PubMed  CAS  Google Scholar 

  63. Janeway CA, Jr. A tale of two T cells. Immunity 1998; 8: 391–4.

    Article  PubMed  CAS  Google Scholar 

  64. van Meerwijk JPM, Marguerat S, Lees RK, Germain RN, Fowlkes BJ, MacDonald HR. Quantitative impact of thymic clonal deletion on the T cell repertoire. J Exp Med 1997; 185: 377–84.

    Article  PubMed  Google Scholar 

  65. Simpson E, Takacs K, Altmann DM. Thymic repertoire selection by superantigens: presentation by human and mouse MHC molecules. Thymus 1994; 23: 1–13.

    PubMed  CAS  Google Scholar 

  66. Abe R, Vacchio MS, Fox B, Hodes RJ. Preferential expression of the T-cell receptor V beta 3 gene by Mlsc reactive T cells. Nature 1988; 335: 827–30.

    Article  PubMed  CAS  Google Scholar 

  67. Choi YW, Herman A, DiGiusto D, Wade T, Marrack P, Kappler J. Residues of the variable region of the T-cell-receptor beta-chain that interact with S. aureus toxin superantigens. Nature 1990; 346: 471–3.

    Article  PubMed  CAS  Google Scholar 

  68. Choi Y, Kappler JW, Marrack P. A superantigen encoded in the open reading frame of the 3’ long terminal repeat of mouse mammary tumour virus. Nature 1991; 350: 203–7.

    Article  PubMed  CAS  Google Scholar 

  69. Kappler JW, Staerz U, White J, Marrack PC. Self-tolerance eliminates T cells specific for Mlsmodified products of the major histocompatibility complex. Nature 1988; 332: 35–40.

    Article  PubMed  CAS  Google Scholar 

  70. Pullen AM, Marrack P, Kappler JW. The T-cell repertoire is heavily influenced by tolerance to polymorphic self-antigens. Nature 1988; 335: 796–801.

    Article  PubMed  CAS  Google Scholar 

  71. Jenkinson EJ, Anderson G, Owen JJT. Studies on T-cell maturation on defined thymic stromal cells in vitro. J Exp Med 1992; 176: 845–53.

    Article  PubMed  CAS  Google Scholar 

  72. Baccala R, Vandekerckhove BA, Jones D, Kono DH, Roncarolo MG, Theofilopoulos AN. Bacterial superantigens mediate T cell deletions in the mouse severe combined immunodeficiency-human liver/thymus model. J Exp Med 1993; 177: 1481–5.

    Article  PubMed  CAS  Google Scholar 

  73. Waller EK, Sen-Majumdar A, Kamel OW, Hansteen GA, Schick MR, Weissman IL. Human T-cell development in SCID-hu mice: staphylococcal enterotoxins induce specific clonal deletions, proliferation, and anergy. Blood 1992; 80: 3144–56.

    PubMed  CAS  Google Scholar 

  74. Komanduri KV, Salha MD, Sékaly RP, McCune JM. Superantigen-mediated deletion of specific T cell receptor V beta subsets in the SCID-hu Thy/Liv mouse is induced by staphylococcal enterotoxin B, but not HIV-1. J Immunol 1997; 158: 544–9.

    PubMed  CAS  Google Scholar 

  75. Owen JJ, Moore NC. Thymocyte-stromal-cell interactions and T-cell selection. Immunol Today 1995; 16: 336–8.

    Article  PubMed  CAS  Google Scholar 

  76. Sprent J, Webb SR. Intrathymic and extrathymic clonal deletion of T cells. Cuff Opin Immunol 1995; 7: 196–205.

    Article  CAS  Google Scholar 

  77. Vandekerckhove BA, Namikawa R, Bacchetta R, Roncarolo MG. Human hematopoietic cells and thymic epithelial cells induce tolerance via different mechanisms in the SCID-hu mouse thymus. J Exp Med 1992; 175: 1033–43.

    Article  PubMed  CAS  Google Scholar 

  78. Klein L, Klein T, Rüther U, Kyewski B. CD4 T cell tolerance to human C-reactive protein, an inducible serum protein, is mediated by medullary thymic epithelium. J Exp Med 1998; 188: 5–16.

    Article  PubMed  CAS  Google Scholar 

  79. Pugliese A, Zeller M, Fernandez JA, Zalcberg LJ, Bartlett RJ, Ricordi C, et al. The insulin gene is transcribed in the human thymus and transcription levels correlate with allelic variation at the INS VNTR-IDDM2 susceptibility locus for type 1 diabetes. Nat Genet 1997; 15: 293–7.

    Article  PubMed  CAS  Google Scholar 

  80. Vafiadis P, Bennet ST, Todd JA, Nadeau J, Grabs R, Goodyer CG, et al. Insulin expression in human thymus is modulated by INS VNTR alleles at the IDDM2 locus. Nat Genet 1997; 15: 289–92.

    Article  PubMed  CAS  Google Scholar 

  81. Egwuagu CE, Charukamnoetkanok P, Gery I. Thymic expression of autoantigens correlates with resistance to autoimmune disease. J Immunol 1997; 159: 3109–12.

    PubMed  CAS  Google Scholar 

  82. Heath V, Mason D, Ramirez F, Seddon B. Homeostatic mechanisms in the control of autoimmunity. Semin Immunol 1997; 9: 375–80.

    Article  PubMed  CAS  Google Scholar 

  83. Anderson G, Moore NC, Owen JJ, Jenkinson EJ. Cellular interactions in thymocyte development. Annu Rev Immunol 1996; 14: 73–99.

    Article  PubMed  CAS  Google Scholar 

  84. Boyd RL, Tucek CL, Godfrey DI, Izon DJ, Wilson TJ, Davidson NJ, et al. The thymic microenvironment. Immunol Today 1993; 14: 445–59.

    Article  PubMed  CAS  Google Scholar 

  85. Denning SM, Kurtzberg J, Le PT, Tuck DT, Singer KH, Haynes BE Human thymic epithelial cells directly induce activation of autologous immature thymocytes. Proc Natl Acad Sci USA 1988; 85: 3125–9.

    Article  PubMed  CAS  Google Scholar 

  86. Berkowitz RD, Alexander S, Bare C, Linquist-Stepps V, Bogan M, Moreno ME, et al. CCR5 and CXCR4-utilizing strains of human immunodeficiency virus type 1 exhibit differential tropism and pathogenesis in vivo. J Virol 1998; 72: 10108–17.

    PubMed  CAS  Google Scholar 

  87. Namen AE, Lupton S, Hjerrild K, Wignall J, Mochizuki DY, Schmierer A, et al. Stimulation of B-cell progenitors by cloned murine interleukin-7. Nature 1988; 333: 571–3.

    Article  PubMed  CAS  Google Scholar 

  88. Komschlies KL, Grzegorzewski KJ, Wiltrout RH. Diverse immunological and hematological effects of interleukin 7: implications for clinical application. J Leuk Biol 1995; 58: 623–33.

    CAS  Google Scholar 

  89. Sudo T, Nishikawa S, Ohno N, Akiyama N, Tamakoshi M, Yoshida H. Expression and function of the interleukin 7 receptor in murine lymphocytes. Proc Natl Acad Sci USA 1993; 90: 9125–9.

    Article  PubMed  CAS  Google Scholar 

  90. Maraskovsky E, O’Reilly LA, Teepe M, Corcoran LM, Peschon JJ, Strasser A. Bc1–2 can rescue T lymphocyte development in interleukin-7 receptor-deficient mice but not in mutant rag-1-/- mice. Cell 1997; 89: 1011–9.

    Article  PubMed  CAS  Google Scholar 

  91. Akashi K, Kondo M, von Freeden-Jeffry U, Murray R, Weissman IL. Bc1–2 rescues T lymphopoiesis in interleukin-7 receptor-deficient mice. Cell 1997; 89: 1033–41.

    Article  PubMed  CAS  Google Scholar 

  92. Schmitt C, Ktorza S, Sarun S, Blanc C, De Jong R, Debre P. CD34-expressing human thymocyte precursors proliferate in response to interleukin-7 but have lost myeloid differentiation potential. Blood 1993; 82: 3675–85.

    PubMed  CAS  Google Scholar 

  93. Varas A, Vicente A, Sacedón R, Zapata AG. Interleukin-7 influences the development of thymic dendritic cells. Blood 1998; 92: 93–100.

    PubMed  CAS  Google Scholar 

  94. Bolotin E, Smogorzewska M, Smith S, Widmer M, Weinberg K. Enhancement of thymopoiesis after bone marrow transplant by in vivo interleukin-7. Blood 1996; 88: 1887–94.

    PubMed  CAS  Google Scholar 

  95. Napolitano LA, Grant RM, Schmidt DK, De Rosa SC, Herzenberg LA, Deeks SG et al. Circulating interleukin-7 levels are correlated with CD4+ lymphopenia and viral load in HIV-1 infected individuals: implications for disease progression. Nature Med 2001; 7: 73–9.

    Article  PubMed  CAS  Google Scholar 

  96. Fry TJ, Connick E, Landay A, Lederman MM, Wood LV, Yarchoan R, Mackall CL. A potential role for IL-7 in T-cell homeostasis in HIV-infected patients. 7th Conf on Retrovirus & Opportunistic Infections presented at San Francisco, 2000.

    Google Scholar 

  97. Lyman SD. Biology of flt3 ligand and receptor. Int J Hematol 1995; 62: 63–73.

    Article  PubMed  CAS  Google Scholar 

  98. Lyman SD, James L, Vanden Bos T, de Vries P, Brasel K, Gliniak B, et al. Molecular cloning of a ligand for the flt3/flk-2 tyrosine kinase receptor: a proliferative factor for primitive hematopoietic cells. Cell 1993; 75: 1157–67.

    Article  PubMed  CAS  Google Scholar 

  99. Lyman SD, Jacobsen SE. c-kit ligand and Flt3 ligand: stem/progenitor cell factors with overlapping yet distinct activities. Blood 1998; 91: 1101–34.

    PubMed  CAS  Google Scholar 

  100. Rodewald HR, Kretzschmar K, Swat W, Takeda S. Intrathymically expressed c-kit ligand (stem cell factor) is a major factor driving expansion of very immature thymocytes in vivo. Immunity 1995; 3: 313–9.

    Article  PubMed  CAS  Google Scholar 

  101. Rodewald HR, Ogawa M, Haller C, Waskow C, DiSanto JP. Pro-thymocyte expansion by c-kit and the common cytokine receptor gamma chain is essential for repertoire formation. Immunity 1997; 6: 265–72.

    Article  PubMed  CAS  Google Scholar 

  102. Moore TA, Zlotnik A. Differential effects of Flk-2/Flt-3 ligand and stem cell factor on murine thymic progenitor cells. J Immunol 1997; 158: 4187–92.

    PubMed  CAS  Google Scholar 

  103. Frearson JA, Alexander DR. Protein tyrosine phosphatases in T-cell development, apoptosis and signalling. Immunol Today 1996; 17: 385–91.

    Article  PubMed  CAS  Google Scholar 

  104. Schmedt C, Saijo K, Niidome T, Kuhn R, Aizawa S, Tarakhovsky A. Csk controls antigen receptor-mediated development and selection of T-lineage cells. Nature 1998; 394: 901–4.

    Article  PubMed  CAS  Google Scholar 

  105. Shao H, Kono DH, Chen L-Y, Rubin EM, Kaye J. Induction of the early growth response (Egr) family of transcription factors during thymic selection. J Exp Med 1997; 185: 731–44.

    Article  PubMed  CAS  Google Scholar 

  106. Ting C-N, Olson MC, Barton KP, Leiden JM. Transcription factor GATA-3 is required for development of the T-cell lineage. Nature 1996; 384: 474–8.

    Article  PubMed  CAS  Google Scholar 

  107. Williams O, Norton T, Halligey M, Kioussis D, Brady HJM. The action of bax and bc1–2 on T cell selection. J Exp Med 1998; 188: 1125–33.

    Article  PubMed  CAS  Google Scholar 

  108. Amakawa R, Hakem A, Kundig TM, Matsuyama T, Simard JJ, Timms E, et al. Impaired negative selection of T cells in Hodgkin’s disease antigen CD30-deficient mice. Cell 1996; 84: 551–62.

    Article  PubMed  CAS  Google Scholar 

  109. Bell EB, Sparshott SM, Bunce C. CD4+ T cell memory, CD45R subsets and the persistence of antigen-a unifying concept. Immunol Today 1998; 19: 60–4.

    Article  PubMed  CAS  Google Scholar 

  110. Butcher EC, Picker LJ. Lymphocyte homing and homeostasis. Science 1996; 272: 60–6.

    Article  PubMed  CAS  Google Scholar 

  111. Rothbard JB, Gefter ML. Interactions between immunogenic peptides and MHC proteins. Annu Rev Immunol 1991; 9: 527–65.

    Article  PubMed  CAS  Google Scholar 

  112. Bretscher P. The two-signal model of lymphocyte activation twenty-one years later. Immunol Today 1992; 13: 74–9.

    Article  PubMed  CAS  Google Scholar 

  113. Croft M, Dubey C. Accessory molecule and costimulation requirements for CD4 T cell response. Crit Rev Immunol 1997; 17: 89–118.

    Article  PubMed  CAS  Google Scholar 

  114. Viola A, Lanzavecchia A. T cell activation determined by T cell receptor number and tunable thresholds. Science 1996; 273: 104–6.

    Article  PubMed  CAS  Google Scholar 

  115. Lu L, Qian S, Hershberger PA, Rudert WA, Lynch DH, Thomson AW. Fas ligand (CD95L) and B7 expression on dendritic cells provide counter-regulatory signals for T cell survival and proliferation. J Immunol 1997; 158: 5676.

    PubMed  CAS  Google Scholar 

  116. McLeod JD, Walker LSK, Patel YI, Boulougouris G, Sansom DM. Activation of human T cells with superantigen (staphylococcal enterotoxin B) and CD28 confers resistance to apoptosis via CD95. J Immunol 1998; 160: 2072–79.

    PubMed  CAS  Google Scholar 

  117. Ahmed R, Gray D. Immunological memory and protective immunity: understanding their relation. Science 1996; 272: 54–60.

    Article  PubMed  CAS  Google Scholar 

  118. Farber DL. Differential TCR signaling and the generation of memory T cells. J Immunol 1998; 160: 535–9.

    PubMed  CAS  Google Scholar 

  119. Sprent J, Tough DF. Lymphocyte life-span and memory. Science 1994; 265: 1395–400.

    Article  PubMed  CAS  Google Scholar 

  120. Farber DL, Acuto O, Bottomly K. Differential T cell receptor-mediated signaling in naive and memory CD4 T cells. Eur J Immunol 1997; 27: 2094–101.

    Article  PubMed  CAS  Google Scholar 

  121. Busch DH, Pilip I, Pamer EG. Evolution of a complex T cell receptor repertoire during primary and recall bacterial infection. J Exp Med 1998; 188: 61–70.

    Article  PubMed  CAS  Google Scholar 

  122. Sourdive DJ, Murali-Krishna K, Altman JD, Zajac AJ, Whitmire JK, Pannetier C, et al. Conserved T cell receptor repertoire in primary and memory CD8 T cell responses to an acute viral infection. J Exp Med 1998; 188: 71–82.

    Article  PubMed  CAS  Google Scholar 

  123. Ogg GS, McMichael AJ. HLA-peptide tetrameric complexes. Curr Opin Immunol 1998; 10: 393–6.

    Article  PubMed  CAS  Google Scholar 

  124. Sallusto F, Lenig D, Forster R, Lipp M, Lanzavecchia A. Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature 1999; 401: 708–12.

    Article  PubMed  CAS  Google Scholar 

  125. Michie CA, McLean A, Alcock C, Beverley PC. Lifespan of human lymphocyte subsets defined by CD45 isoforms. Nature 1992; 360: 264–5.

    Article  PubMed  CAS  Google Scholar 

  126. Bunce C, Bell EB. CD45RC isoforms define two types of CD4 memory T cells, one of which depends on persisting antigen. J Exp Med 1997; 185: 767–76.

    Article  PubMed  CAS  Google Scholar 

  127. Roederer M, Dubs JG, Anderson MT, Raju PA, Herzenberg LA. CD8 naive T cell counts decrease progressively in HIV-infected adults. J Clin Invest 1995; 95: 2061–6.

    Article  PubMed  CAS  Google Scholar 

  128. Richards D, Chapman MD, Sasama J, Lee TH, Kemeny DM. Immune memory in CD4+ CD45RA+ T cells. Immunology 1997; 91: 331–9.

    Article  PubMed  CAS  Google Scholar 

  129. Abbas A, Murphy KM, Sher A. Functional diversity of helper T lymphocytes. Nature 1996; 383: 787–93.

    Article  PubMed  CAS  Google Scholar 

  130. Romagnani S. The Thl/Th2 paradigm. Immunol Today 1997; 18: 263–6.

    Article  PubMed  CAS  Google Scholar 

  131. Clerici M, Shearer G. The Thl-Th2 hypothesis of HIV infection: new insights. Immunol Today 1994; 15: 575–81.

    Article  PubMed  CAS  Google Scholar 

  132. Mitra DK, De Rosa SC, Luke A, Balamurugan A, Khaitan BK, Tung J, et al. Differential representations of memory T cell subsets are characteristic of polarized immunity in leprosy and atopic diseases. Int Immunol 1999; 11: 1801–10.

    Article  PubMed  CAS  Google Scholar 

  133. Lee PP, Yee C, Savage PA, Fong L, Brockstedt D, Weber JS, et al. Characterization of circulating T cells specific for tumor-associated antigens in melanoma patients. Nat Med 1999; 5: 677–85.

    Article  PubMed  CAS  Google Scholar 

  134. Ridge JP, Di Rosa F, Matzinger P. A conditioned dendritic cell can be a temporal bridge between a CD4+ T-helper and a T-killer cell. Nature 1998; 393: 474–8.

    Article  PubMed  CAS  Google Scholar 

  135. Bennett SR, Carbone FR, Karamalis F, Flavell RA, Miller JF, Heath WR. Help for cytotoxic-Tcell responses is mediated by CD40 signalling. Nature 1998; 393: 478–80.

    Article  PubMed  CAS  Google Scholar 

  136. Schoenberger SP, Toes RE, van der Voort EI, Offringa R, Melief CJ. T-cell help for cytotoxic T lymphocytes is mediated by CD40–CD40L interactions. Nature 1998; 393: 480–3.

    Article  PubMed  CAS  Google Scholar 

  137. Mackey MF, Gunn JR, Maliszewsky C, Kikutani H, Noelle RJ, Barth RJ Jr. Dendritic cells require maturation via CD40 to generate protective antitumor immunity. J Immunol 1998; 161: 2094–8.

    PubMed  CAS  Google Scholar 

  138. Lord GM, Matarese G, Howard LK, Baker RJ, Bloom SR, Lechler RI. Leptin modulates the T-cell immune response and reverses starvation-induced immunosuppression. Nature 1998; 394: 897–901.

    Article  PubMed  CAS  Google Scholar 

  139. Munn DH, Zhou M, Attwood JT, Bondarev I, Conway SJ, Marshall B, et al. Prevention of allogeneic fetal rejection by tryptophan catabolism. Science 1998; 281: 1191–3.

    Article  PubMed  CAS  Google Scholar 

  140. Adleman LM, Wofsy D. T cell homeostasis: implications in HIV infection. J AIDS 1993; 6: 144–52.

    CAS  Google Scholar 

  141. Margolick JB, Donnenberg AD. T-cell homeostasis in HIV-1 infection. Semin Immunol 1997; 9: 381–8.

    Article  PubMed  CAS  Google Scholar 

  142. Mehr R, Perelson AS, Fridkis-Hareli M, Globerson A. Regulatory feedback pathways in the thymus. Immunol Today 1997; 18: 581–5.

    Article  PubMed  CAS  Google Scholar 

  143. Mehr R, Perelson AS. Blind T-cell homeostasis and the CD4/CD8 ratio in the thymus and peripheral blood. J AIDS Hum Retrovirol 1997; 14: 387–98.

    CAS  Google Scholar 

  144. Bell EB, Sparshott SM. The peripheral T-cell pool: regulation by non-antigen induced proliferation? Semin Immunol 1997; 9: 347–53.

    Article  PubMed  CAS  Google Scholar 

  145. Tanchot C, Rocha B. The peripheral T cell repertoire: independent homeostatic regulation of virgin and activated CD8+ T cell pools. Eur J Immunol 1995; 25: 2127–36.

    Article  PubMed  CAS  Google Scholar 

  146. Mackall CL, Gress RE. Pathways of T-cell regeneration in mice and humans: implications for bone marrow transplantation and immunotherapy. Immunol Rev 1997; 157: 61–72.

    Article  PubMed  CAS  Google Scholar 

  147. Mackall CL, Hakim FT, Gress RE. Restoration of T-cell homeostasis after T-cell depletion. Semin Immunol 1997; 9: 339–46.

    Article  PubMed  CAS  Google Scholar 

  148. Mackall CL, Granger L, Sheard MA, Cepeda R, Gress RE. T-cell regeneration after bone marrow transplantation: differential CD45 isoform expression on thymic-derived versus thymic-independent progeny. Blood 1993; 82: 2585–94.

    PubMed  CAS  Google Scholar 

  149. Mackall CL, Bare CV, Granger LA, Sharrow SO, Titus JA, Gress RE. Thymic-independent T cell regeneration occurs via antigen-driven expansion of peripheral T cells resulting in a repertoire that is limited in diversity and prone to skewing. J Immunol 1996; 156: 4609–16.

    PubMed  CAS  Google Scholar 

  150. Waldrop SL, Pitcher CJ, Peterson DM, Maino VC, Picker LJ. Determination of antigen-specific memory/effector CD4+T cell frequencies by flow cytometry: evidence for a novel, antigen-specific homeostatic mechanism in HIV-associated immunodeficiency. J Clin Invest 1997; 99: 1739–50.

    Article  PubMed  CAS  Google Scholar 

  151. McCune JM. Thymic function in HIV-1 disease. Semin Immunol 1997; 9 (6): 397–404.

    Article  PubMed  CAS  Google Scholar 

  152. Steinmann GG. Changes in the human thymus during aging. Curr Top Pathol 1986; 75: 43–88.

    Article  PubMed  CAS  Google Scholar 

  153. Moore AV, Korobkin M, Olanow W, Heaston DK, Ram PC, Dunnick NR, Silverman PM. Age-related changes in the thymus gland: CT-pathologic correlation. AJR 1983; 141: 241–6.

    PubMed  CAS  Google Scholar 

  154. Francis IR, Glazer GM, Brookstein FL, Gross BH. The thymus: reexamination of age-related changes in size and shape. Am J Roentgenol 1985; 145: 249–54.

    CAS  Google Scholar 

  155. Dixon AK, Hilton CJ, Williams GT. Computed tomography and histological correlation of the thymic remnant. Clin Radiol 1981; 32: 255–7.

    Article  PubMed  CAS  Google Scholar 

  156. Lum LG. The kinetics of immune reconstitution after human marrow transplantation. Blood 1987; 69: 369–80.

    PubMed  CAS  Google Scholar 

  157. Parkman R, Weinberg KI. Immunological reconstitution following bone marrow transplantation. Immunol Rev 1997; 157: 73–8.

    Article  PubMed  CAS  Google Scholar 

  158. Guillaume T, Rubinstein DB, Symann M. Immune reconstitution and immunotherapy after autologous hematopoietic stem cell transplantation. Blood 1998; 92: 1471–90.

    PubMed  CAS  Google Scholar 

  159. Choyke PL, Zeman RK, Gootenberg JE, Greenberg JN, Hoffer F, Frank JA. Thymic atrophy and regrowth in response to chemotherapy: CT evaluation. Am J Roentgenol 1987; 149: 269–72.

    CAS  Google Scholar 

  160. Small EJ, Venook AP, Damon LE. Gallium-avid thymic hyperplasia in an adult after chemotherapy for Hodgkin disease. Cancer 1993; 72: 905–8.

    Article  PubMed  CAS  Google Scholar 

  161. Miniero R, Busca A, Leonardo E, Mossetti C, Machado D, Vassallo E, Madon E. Rebound thymic hyperplasia following high dose chemotherapy and allogeneic BMT. Bone Marrow Transplant 1993; 11: 67–70.

    PubMed  CAS  Google Scholar 

  162. Chertoff J, Barth RA, Dickerman JD. Rebound thymic hyperplasia five years after chemotherapy for Wilms’ tumor. Pediatr Radiol 1991; 21: 596–7.

    Article  PubMed  CAS  Google Scholar 

  163. Mackall CL, Fleisher TA, Brown MR, Andrich MP, Chen CC, Feuerstein IM, et al. Age, thymopoiesis, and CD4+ T-lymphocyte regeneration after intensive chemotherapy. N Engl J Med 1995; 332: 143–9.

    Article  PubMed  CAS  Google Scholar 

  164. Roederer M, De Rosa SC, Watanabe N, Herzenberg LA. Dynamics of fine T-cell subsets during HIV disease and after thymic ablation by mediastinal irradiation. Semin Immunol 1997; 9: 389–96.

    Article  PubMed  CAS  Google Scholar 

  165. Watanabe N, De Rosa SC, Cmelak A, Hoppe R, Herzenberg LA, Roederer M. Long-term depletion of naive T cells in patients treated for Hodgkin’s disease. Blood 1997; 90: 3662–72.

    PubMed  CAS  Google Scholar 

  166. Beagley KW, Husband AJ. Intraepithelial lymphocytes: origins, distribution, and function. Crit Rev Immunol 1998; 18: 237–54.

    Article  PubMed  CAS  Google Scholar 

  167. Clegg CH, Rulffes JT, Wallace PM, Haugen HS. Regulation of an extrathymic T-cell development pathway by oncostatin M. Nature 1996; 384: 261–3.

    Article  PubMed  CAS  Google Scholar 

  168. Garcia-Ojeda ME, Dejbakhsh-Jones S, Weissman IL, Strober S. An alternate pathway for T cell development supported by the bone marrow microenvironment: recapitulation of thymic maturation. J Exp Med 1998; 187: 1813–23.

    Article  PubMed  CAS  Google Scholar 

  169. Heitger A, Neu N, Kern H, Panzer-Grümayer ER, Greinix H, Nachbaur D, et al. Essential role of the thymus to reconstitute naive (CD45RA+) T-helper cells after human allogeneic bone marrow transplantation. Blood 1997; 90: 850–7.

    PubMed  CAS  Google Scholar 

  170. Mackall CL, Fleisher TA, Brown MR, Andrich MP, Chen CC, Feuerstein IM, et al. Distinctions between CD8+ and CD4+ T-cell regenerative pathways result in prolonged T-cell subset imbalance after intensive chemotherapy. Blood 1997; 89: 3700–7.

    PubMed  CAS  Google Scholar 

  171. Hellerstein MK, McCune JM. T cell turnover in HIV-1 disease. Immunity 1997; 7: 583–9.

    Article  PubMed  CAS  Google Scholar 

  172. McCune JM, Loftus R, Schmidt DK, Carroll P, Webster D, Swor-Yim LB, et al. High prevalence of thymic tissue in adults with human immunodeficiency virus-1 infection. J Clin Invest 1998; 101: 2301–8.

    Article  PubMed  CAS  Google Scholar 

  173. Rabin RL, Roederer M, Maldonado Y, Petru A, Herzenberg LA. Altered representation of naive and memory CD8 T cell subsets in HIV-infected children. J Clin Invest 1995; 95: 2054–60.

    Article  PubMed  CAS  Google Scholar 

  174. Macallan DC, Fullerton CA, Neese RA, Haddock K, Park SS, Hellerstein MK. 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 USA 1998; 95: 708–13.

    Article  PubMed  CAS  Google Scholar 

  175. Hellerstein M, Hanley MB, Cesar D, Siler S, Papageorgopoulos C, Wieder E, et al. Directly measured kinetics of circulating T lymphocytes in normal and HIV-1-infected humans. Nat Med 1999; 5: 83–9.

    Article  PubMed  CAS  Google Scholar 

  176. McCune JM, Hanley MB, Cesar D, Halvorsen R, Hoh R, Schmidt D, et al. Factors influencing T-cell turnover in HIV-1-seropositive patients. J Clin Invest 2000; 105: R1–8.

    Article  PubMed  CAS  Google Scholar 

  177. Arstila TP, Casrouge A, Baron V, Even J, Kanellopoulos J, Kourilsky P. A direct estimate of the human alphabeta T cell receptor diversity. Science 1999; 286: 958–61.

    Article  PubMed  CAS  Google Scholar 

  178. Lewis SM. The mechanism of V(D)J joining: lessons from molecular, immunological, and cornparative analyses. Adv Immunol 1994; 56: 27–150.

    Article  PubMed  CAS  Google Scholar 

  179. Lewis SM, Wu GE. The origins of V(D)J recombination. Cell 1997; 88: 159–62.

    Article  PubMed  CAS  Google Scholar 

  180. Douek DC, McFarland RD, Keiser PH, Gage EA, Massey JM, Haynes BF, et al. Changes in thymic function with age and during the treatment of HIV infection. Nature 1998; 396: 690–5.

    Article  PubMed  CAS  Google Scholar 

  181. Poulin JF, Viswanathan MN, Harris JM, Komanduri KV, Wieder E, Ringuette N, et al. Direct evidence for thymic function in adult humans. J Exp Med 1999; 190: 479–86.

    Article  PubMed  CAS  Google Scholar 

  182. Zhang L, Lewin SR, Markowitz M, Lin HH, Skulsky E, Karanicolas R, et al. Measuring recent thymic emigrants in blood of normal and HIV-1—infected individuals before and after effective therapy. J Exp Med 1999; 190: 725–32.

    Article  PubMed  CAS  Google Scholar 

  183. Hatzakis A, Touloumi G, Karanicolas R, Karafoulidou A, Mandalaki T, Anastassopopoulou C, et al. Effect of recent thymic emigrants on progression of HIV-1 disease. Lancet 2000; 355: 599–604.

    Article  PubMed  CAS  Google Scholar 

  184. Douek DC, Vescio RA, Betts MR, Brenchley JM, Hill BJ, Zhang L, et al. Assessment of thymic output in adults after haematopoietic stem—cell transplant and prediction of T cell reconstitution. Lancet 2000; 355: 1875–81.

    Article  PubMed  CAS  Google Scholar 

  185. Su L, Kaneshima H, Bonyhadi M, Salimi S, Kraft D, Rabin L, McCune JM. HIV-1—induced thymocyte depletion is associated with indirect cytopathogenicity and infection of progenitor cells in vivo. Immunity 1995; 2: 25–36.

    Article  PubMed  CAS  Google Scholar 

  186. Jenkins M, Hanley MB, Moreno MB, Wieder E, McCune JM. Human immunodeficiency virus-1 infection interrupts thymopoiesis and multilineage hematopoiesis in vivo. Blood 1998; 91: 2672–8.

    PubMed  CAS  Google Scholar 

  187. McCune JM. Animal models of HIV-1 disease. Science 1997; 278: 2141–2.

    Article  PubMed  CAS  Google Scholar 

Download references

Authors
  1. Krishna V. Komanduri
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Joseph M. McCune
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Hospital de Beaumont, Lausanne, Switzerland

    Giuseppe Pantaleo MD

  2. Partners AIDS Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Bruce D. Walker MD

Rights and permissions

Reprints and permissions

Copyright information

© 2001 Humana Press Inc., Totowa, NJ

About this chapter

Cite this chapter

Komanduri, K.V., McCune, J.M. (2001). Development and Reconstitution of T-Lymphoid Immunity. In: Pantaleo, G., Walker, B.D. (eds) Retroviral Immunology. Infectious Disease. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-59259-110-7_4

Download citation

  • DOI: https://doi.org/10.1007/978-1-59259-110-7_4

  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-61737-128-8

  • Online ISBN: 978-1-59259-110-7

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation