Advertisement

Physiology and Immunology of the Thymus Gland

  • Milena Nasi
  • Marcello Pinti
  • Leonarda Troiano
  • Andrea Cossarizza

Abstract

The thymus is a gland located in the upper anterior portion of the chest cavity just behind the sternum. Under the evolutionary pressure exerted by the emergence of adaptive immunity and its inherent risk to form receptors that recognize self molecules, this gland appeared about 500 million years ago as a novel structure that had the role of instructing T-cells in order to prevent autoimmunity and orchestrate self-tolerance. The thymus has thus become a crucial lymphoid organ in which cells arriving from the bone marrow undergo a finely tuned process of selection, based on the specificity of T-cell receptors (TCRs), and differentiate into mature T-cells. The development of thymocytes involves a stringent selection in which only 1–3% of these cells succeed in survival and can leave the gland to colonize the periphery and give origin to effective immune cells [1]–[3]. During the maturation in the thymus, T-cells are first positively selected for “usefulness” [positive selection, driven by the affinity of the clonotypic TCR for Major Histocompatibility Complex (MHC) molecules] and then negatively selected against autoreactivity (negative selection, driven by the recognition of self peptides on self MHC by the TCR, which triggers the process of cell death).

Keywords

Treg Cell Thymic Epithelial Cell Thymic Hormone Thymic Microenvironment Thymosin Beta 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Scollay RG, Butcher EC, Weissman IL (1980) Thymus cell migration. Quantitative aspects of cellular traffic from the thymus to the periphery in mice. Eur J Immunol 10:210–218PubMedCrossRefGoogle Scholar
  2. 2.
    Egerton M, Scollay R, Shortman K (1990) Kinetics of mature T-cell development in the thymus. Proc Natl Acad Sci USA 87:2579–2582PubMedCrossRefGoogle Scholar
  3. 3.
    Goldrath AW, Bevan MJ (1999) Selecting and maintaining a diverse T-cell repertoire. Nature 402:255–262PubMedCrossRefGoogle Scholar
  4. 4.
    Miller JF (2002) The discovery of thymus function and of thymus-derived lymphocytes. Immunol Rev 185:7–14PubMedCrossRefGoogle Scholar
  5. 5.
    Miller JF (1961) Analysis of the thymus influence in leukaemogenesis. Nature 191:248–249PubMedCrossRefGoogle Scholar
  6. 6.
    Miller JF (1961) Immunological function of the thymus. Lancet 2:748–749PubMedCrossRefGoogle Scholar
  7. 7.
    Miller JF (1965) The role of the thymus in immune processes. Int Arch Allergy Appl Immunol 28:61–70PubMedGoogle Scholar
  8. 8.
    Miller JF (1967) The thymus. Yesterday, today, and tomorrow. Lancet 2:1299–1302PubMedCrossRefGoogle Scholar
  9. 9.
    Takahama Y (2006) Journey through the thymus: Stromal guides for T-cell development and selection. Nat Rev Immunol 6:127–135PubMedCrossRefGoogle Scholar
  10. 10.
    Owen JJ, Ritter MA (1969) Tissue interaction in the development of thymus lymphocytes. J Exp Med 129:431–442PubMedCrossRefGoogle Scholar
  11. 11.
    Haynes BF, Heinly CS (1995) 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 181:1445–1458PubMedCrossRefGoogle Scholar
  12. 12.
    Lind EF, Prockop SE, Porritt HE, Petrie HT (2001) Mapping precursor movement through the postnatal thymus reveals specific microenvironments supporting defined stages of early lymphoid development. J Exp Med 194:127–134PubMedCrossRefGoogle Scholar
  13. 13.
    Rossi FM, Corbel SY, Merzaban JS et al (2005) Recruitment of adult thymic progenitors is regulated by Pselectin and its ligand PSGL-1. Nat Immunol 6:626–634PubMedCrossRefGoogle Scholar
  14. 14.
    Le Douarin NM, Jotereau FV (1975) Tracing of cells of the avian thymus through embryonic life in interspecific chimeras. J Exp Med 142:17–40PubMedCrossRefGoogle Scholar
  15. 15.
    Havran WL, Allison JP (1988) Developmentally ordered appearance of thymocytes expressing different T-cell antigen receptors. Nature 335:443–445PubMedCrossRefGoogle Scholar
  16. 16.
    Foss DL, Donskoy E, Goldschneider I (2001) The importation of hematogenous precursors by the thymus is a gated phenomenon in normal adult mice. J Exp Med 193:365–374PubMedCrossRefGoogle Scholar
  17. 17.
    Ladi E, Yin X, Chtanova T, Robey EA (2006) Thymic microenvironments for T cell differentiation and selection. Nat Immunol 7:338–343PubMedCrossRefGoogle Scholar
  18. 18.
    Plotkin J, Prockop SE, Lepique A, Petrie HT (2003) Critical role for CXCR4 signaling in progenitor localization and T cell differentiation in the postnatal thymus. J Immunol 171:4521–4527PubMedGoogle Scholar
  19. 19.
    Misslitz A, Pabst O, Mintzen J et al (2004) Thymic T cell development and progenitor localization depend on CCR7. J Exp Med 200:481–491PubMedCrossRefGoogle Scholar
  20. 20.
    Benz C, Heinzel K, Bleul CC (2004) Homing of immature thymocytes to the subcapsular microenvironment within the thymus is not an absolute requirement for T cell development. Eur J Immunol 34:3652–3663PubMedCrossRefGoogle Scholar
  21. 21.
    Raulet DH, Garman RD, Saito H, Tonegawa S (1985) Developmental regulation of T-cell receptor gene expression. Nature 314:103–107PubMedCrossRefGoogle Scholar
  22. 22.
    von Boehmer H, Fehling HJ (1997) Structure and function of the pre-T cell receptor. Annu Rev Immunol 15:433–452CrossRefGoogle Scholar
  23. 23.
    Irving BA, Alt FW, Killeen N (1998) Thymocyte development in the absence of pre-T cell receptor extracellular immunoglobulin domains. Science 280:905–908PubMedCrossRefGoogle Scholar
  24. 24.
    Ciofani M, Zuniga-Pflucker JC (2005) Notch promotes survival of pre-T cells at the beta-selection checkpoint by regulating cellular metabolism. Nat Immunol 6:881–888PubMedCrossRefGoogle Scholar
  25. 25.
    Takahama Y, Letterio JJ, Suzuki H et al (1994) Early progression of thymocytes along the CD4/CD8 developmental pathway is regulated by a subset of thymic epithelial cells expressing transforming growth factor beta. J Exp Med 179:1495–1506PubMedCrossRefGoogle Scholar
  26. 26.
    Hollander GA et al (1995) Developmental control point in induction of thymic cortex regulated by a subpopulation of prothymocytes. Nature 373:350–353PubMedCrossRefGoogle Scholar
  27. 27.
    van Ewijk W, Hollander G, Terhorst C, Wang B (2000) Stepwise development of thymic microenvironments in vivo is regulated by thymocyte subsets. Development 127:1583–1591PubMedGoogle Scholar
  28. 28.
    Klug DB, Carter C, Crouch E et al (1998) Interdependence of cortical thymic epithelial cell differentiation and T-lineage commitment. Proc Natl Acad Sci USA 95:11822–11827PubMedCrossRefGoogle Scholar
  29. 29.
    Klug DB, Carter C, Gimenez-Conti IB, Richie ER (2002) Cutting edge: Thymocyte-independent and thymocyte-dependent phases of epithelial patterning in the fetal thymus. J Immunol 169:2842–2845PubMedGoogle Scholar
  30. 30.
    Witt CM, Raychaudhuri S, Schaefer B et al (2005) Directed migration of positively selected thymocytes visualized in real time. PLoS Biol 3:e160PubMedCrossRefGoogle Scholar
  31. 31.
    Bousso P, Bhakta NR, Lewis RS, Robey E (2002) Dynamics of thymocyte-stromal cell interactions visualized by two-photon microscopy. Science 296:1876–1880PubMedCrossRefGoogle Scholar
  32. 32.
    Guidos C (2006) Thymus and T-lymphocyte development: What is new in the 21st century? Immunol Rev 209:5–9PubMedCrossRefGoogle Scholar
  33. 33.
    Bleul CC, Boehm T (2000) Chemokines define distinct microenvironments in the developing thymus. Eur J Immunol 30:3371–3379PubMedCrossRefGoogle Scholar
  34. 34.
    Campbell JJ, Butcher EC (2000) Chemokines in tissue-specific and microenvironment-specific lymphocyte homing. Curr Opin Immunol 12:336–341PubMedCrossRefGoogle Scholar
  35. 35.
    Reichert RA, Weissman IL, Butcher EC (1986) Phenotypic analysis of thymocytes that express homing receptors for peripheral lymph nodes. J Immunol 136:3521–3528PubMedGoogle Scholar
  36. 36.
    Bendelac A, Matzinger P, Seder RA et al (1992) Activation events during thymic selection. J Exp Med 175:731–742PubMedCrossRefGoogle Scholar
  37. 37.
    Ramsdell F, Jenkins M, Dinh Q, Fowlkes BJ (1991) The majority of CD4+8-thymocytes are functionally immature. J Immunol 147:1779–1785PubMedGoogle Scholar
  38. 38.
    Kyewski B, Derbinski J (2004) Self-representation in the thymus: An extended view. Nat Rev Immunol 4:688–698PubMedCrossRefGoogle Scholar
  39. 39.
    Derbinski J et al (2005) Promiscuous gene expression in thymic epithelial cells is regulated at multiple levels. J Exp Med 202:33–45PubMedCrossRefGoogle Scholar
  40. 40.
    Zuklys S, Balciunaite G, Agarwal A et al (2000) Normal thymic architecture and negative selection are associated with Aire expression, the gene defective in the autoimmune-polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). J Immunol 165:1976–1983PubMedGoogle Scholar
  41. 41.
    Aaltonen J et al (1997) High-resolution physical and transcriptional mapping of the autoimmune polyen-docrinopathy-candidiasis-ectodermal dystrophy locus on chromosome 21q22.3 by FISH. Genome Res 7:820–829PubMedGoogle Scholar
  42. 42.
    Nagamine K, Peterson P, Scott HS et al (1997) Positional cloning of the APECED gene. Nat Genet 17:393–398PubMedCrossRefGoogle Scholar
  43. 43.
    Anderson MS, Venanzi S, Klein L et al (2002) Projection of an immunological self shadow within the thymus by the aire protein. Science 298:1395–1401PubMedCrossRefGoogle Scholar
  44. 44.
    Kuroda N, Mitani T, Takeda N et al (2005) Development of autoimmunity against transcriptionally unrepressed target antigen in the thymus of Aire-deficient mice. J Immunol 174:1862–1870PubMedGoogle Scholar
  45. 45.
    Liston A, Lesage S, Wilson J et al (2003) Aire regulates negative selection of organ-specific T cells. Nat Immunol 4:350–354PubMedCrossRefGoogle Scholar
  46. 46.
    Anderson MS, Venanzi ES, Chen Z et al (2005) The cellular mechanism of Aire control of T cell tolerance. Immunity 23:227–239PubMedCrossRefGoogle Scholar
  47. 47.
    Gallegos AM, Bevan MJ (2004) Central tolerance to tissue-specific antigens mediated by direct and indirect antigen presentation. J Exp Med 200:1039–1049PubMedCrossRefGoogle Scholar
  48. 48.
    Fontenot JD, Rasmussen JP, Williams LM et al (2005) Regulatory T cell lineage specification by the forkhead transcription factor Foxp3. Immunity 22:329–341PubMedCrossRefGoogle Scholar
  49. 49.
    Sakaguchi S (2004) Naturally arising CD4+ regulatory T cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol 22:531–562PubMedCrossRefGoogle Scholar
  50. 50.
    Watanabe N et al (2005) Hassall’s corpuscles instruct dendritic cells to induce CD4+CD25+ regulatory T cells in human thymus. Nature 436:1181–1185PubMedCrossRefGoogle Scholar
  51. 51.
    Kato S (1997) Thymic microvascular system. Microsc Res Tech 38:287–299PubMedCrossRefGoogle Scholar
  52. 52.
    Muller KM, Luedecker CJ, Udey MC, Farr AG (1997) Involvement of E-cadherin in thymus organogenesis and thymocyte maturation. Immunity 6:257–264PubMedCrossRefGoogle Scholar
  53. 53.
    Cyster JG (2005) Chemokines, sphingosine-1-phosphate, and cell migration in secondary lymphoid organs. Annu Rev Immunol 23:127–159PubMedCrossRefGoogle Scholar
  54. 54.
    Mandala S, Hajdu R, Bergstrom J et al (2002) Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists. Science 296:346–349PubMedCrossRefGoogle Scholar
  55. 55.
    Wei SH, Rosen H, Matheu MP et al (2005) Sphingosine 1-phosphate type 1 receptor agonism inhibits trans-endothelial migration of medullary T cells to lymph atic sinuses. Nat Immunol 6:1228–1235PubMedCrossRefGoogle Scholar
  56. 56.
    Schwab SR, Pereira JP, Matloubian M et al (2005) Lymphocyte sequestration through S1P lyase inhibition and disruption of S1P gradients. Science 309:1735–1739PubMedCrossRefGoogle Scholar
  57. 57.
    Feng C, Woodside KJ, Vance BA et al (2002) A potential role for CD69 in thymocyte emigration. Int Immunol 14:535–544PubMedCrossRefGoogle Scholar
  58. 58.
    Paust S, Cantor H (2005) Regulatory T cells and autoimmune disease. Immunol Rev 204:195–207PubMedCrossRefGoogle Scholar
  59. 59.
    Sakaguchi S (2005) Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self. Nat Immunol 6:345–352PubMedCrossRefGoogle Scholar
  60. 60.
    Fontenot JD, Gavin MA, Rudensky AY (2003) Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 4:330–336PubMedCrossRefGoogle Scholar
  61. 61.
    Khattri R, Cox T, Yasayko SA, Ramsdell F (2003) An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nat Immunol 4:337–342PubMedCrossRefGoogle Scholar
  62. 62.
    Banham AH (2006) Cell-surface IL-7 receptor expression facilitates the purification of Foxp3(+) regulatory T cells. Trends Immunol 27:541–544PubMedCrossRefGoogle Scholar
  63. 63.
    Borsellino G et al (2007) Expression of ectonucleotidase CD39 by Foxp3+ Treg cells: Hydrolysis of extracellular ATP and immune suppression. Blood 110:1225–1232PubMedCrossRefGoogle Scholar
  64. 64.
    Kleinewietfeld M, Puentes F, Borsellino G et al (2005) CCR6 expression defines regulatory effector/memorylike cells within the CD25(+)CD4+ T-cell subset. Blood 105:2877–2886PubMedCrossRefGoogle Scholar
  65. 65.
    Fontenot JD, Rudensky AY (2005) A well adapted regulatory contrivance: Regulatory T cell development and the forkhead family transcription factor Foxp3. Nat Immunol 6:331–337PubMedCrossRefGoogle Scholar
  66. 66.
    Farr AG, Dooley JL, Erickson M (2002) Organization of thymic medullary epithelial heterogeneity: Implications for mechanisms of epithelial differentiation. Immunol Rev 189:20–27PubMedCrossRefGoogle Scholar
  67. 67.
    Makino Y, Kanno R, Ito T et al (1995) Predominant expression of invariant V alpha 14+ TCR alpha chain in NK1.1+ T cell populations. Int Immunol 7:1157–1161PubMedCrossRefGoogle Scholar
  68. 68.
    Kronenberg M (2005) Toward an understanding of NKT cell biology: Progress and paradoxes. Annu Rev Immunol 23:877–900PubMedCrossRefGoogle Scholar
  69. 69.
    Rosen DB et al (2005) Cutting edge: Lectin-like transcript-1 is a ligand for the inhibitory human NKR-P1A receptor. J Immunol 175:7796–7799PubMedGoogle Scholar
  70. 70.
    Zhou D, Mattner J, Cantu C IIIrd et al (2004) Lysosomal glycosphingolipid recognition by NKT cells. Science 306:1786–1789PubMedCrossRefGoogle Scholar
  71. 71.
    Bendelac A (1995) Positive selection of mouse NK1+ T cells by CD1-expressing cortical thymocytes. J Exp Med 182:2091–2096PubMedCrossRefGoogle Scholar
  72. 72.
    Coles MC, Raulet DH (2000) NK1.1+ T cells in the liver arise in the thymus and are selected by interactions with class I molecules on CD4+CD8+ cells. J Immunol 164:2412–2418PubMedGoogle Scholar
  73. 73.
    Wei DG, Lee H, Park SH et al (2005) Expansion and long-range differentiation of the NKT cell lineage in mice expressing CD1d exclusively on cortical thymocytes. J Exp Med 202:239–248PubMedCrossRefGoogle Scholar
  74. 74.
    Forestier C, Park SH, Wei D et al (2003) T cell development in mice expressing CD1d directed by a classical MHC class II promoter. J Immunol 171:4096–4104PubMedGoogle Scholar
  75. 75.
    Raulet DH (1989) The structure, function, and molecular genetics of the gamma/delta T cell receptor. Annu Rev Immunol 7:175–207PubMedCrossRefGoogle Scholar
  76. 76.
    Haas W, Pereira P, Tonegawa S (1993) Gamma/delta cells. Annu Rev Immunol 11:637–685PubMedGoogle Scholar
  77. 77.
    Allison JP, Havran WL (1991) The immunobiology of T cells with invariant gamma delta antigen receptors. Annu Rev Immunol 9:679–705PubMedGoogle Scholar
  78. 78.
    Hayday AC (2000) Gamma delta cells: A right time and a right place for a conserved third way of protection. Annu Rev Immunol 18:975–1026PubMedCrossRefGoogle Scholar
  79. 79.
    Xiong N, Raulet DH (2007) Development and selection of gammadelta T cells. Immunol Rev 215:15–31PubMedCrossRefGoogle Scholar
  80. 80.
    Haks MC, Lefebvre JM, Lauritsen JP et al (2005) Attenuation of gammadeltaTCR signaling efficiently diverts thymocytes to the alphabeta lineage. Immunity 22:595–606PubMedCrossRefGoogle Scholar
  81. 81.
    Hayes SM, Li L, Love PE (2005) TCR signal strength influences alphabeta/gammadelta lineage fate. Immunity 22:583–593PubMedCrossRefGoogle Scholar
  82. 82.
    Robey E (2005) The alphabeta versus gammadelta T cell fate decision: When less is more. Immunity 22:533–534PubMedCrossRefGoogle Scholar
  83. 83.
    Havran WL, Carbone A, Allison JP (1991) Murine T cells with invariant gamma delta antigen receptors: Origin, repertoire, and specificity. Semin Immunol 3:89–97PubMedGoogle Scholar
  84. 84.
    Ikuta K, Kina T, MacNeil I et al (1990) A developmental switch in thymic lymphocyte maturation potential occurs at the level of hematopoietic stem cells. Cell 62:863–874PubMedCrossRefGoogle Scholar
  85. 85.
    Pennington DJ, Silva-Santos B, Shires J et al (2003) The inter-relatedness and interdependence of mouse T cell receptor gammadelta+ and alphabeta+ cells. Nat Immunol 4:991–998PubMedCrossRefGoogle Scholar
  86. 86.
    Silva-Santos B, Pennington DJ, Hayday AC (2005) Lymphotoxin-mediated regulation of gammadelta cell differentiation by alphabeta T cell progenitors. Science 307:925–928PubMedCrossRefGoogle Scholar
  87. 87.
    Grusby MJ, Auchincloss H Jr, Lee R et al (1993) Mice lacking major histocompatibility complex class I and class II molecules. Proc Natl Acad Sci USA 90:3913–3917PubMedCrossRefGoogle Scholar
  88. 88.
    Correa I, Bix M, Liao NS et al (1992) Most gamma delta T cells develop normally in beta 2-microglobulin-deficient mice. Proc Natl Acad Sci USA 89:653–657PubMedCrossRefGoogle Scholar
  89. 89.
    Bigby M, Markowitz JS, Bleicher PA et al (1993) Most gamma delta T cells develop normally in the absence of MHC class II molecules. J Immunol 151:4465–4475PubMedGoogle Scholar
  90. 90.
    Dardenne M, Pleau JM, Blouquit JY, Bach JF (1980) Characterization of facteur thymique serique (FTS) in the thymus. II. Direct demonstration of the presence of FTS in thymosin fraction V. Clin Exp Immunol 42:477–482PubMedGoogle Scholar
  91. 91.
    Goldstein G (1975) The isolation of thymopoietin (thymin). Ann N Y Acad Sci 249:177–185PubMedCrossRefGoogle Scholar
  92. 92.
    Hooper JA, McDaniel MC, Thurman JB et al (1975) Purification and properties of bovine thymosin. Ann N Y Acad Sci 249:125–144PubMedCrossRefGoogle Scholar
  93. 93.
    Kook AI, Yakir Y, Trainin N (1975) Isolation and partial chemical characterization of THF, a thymus hormone involved in immune maturation of lymphoid cells. Cell Immunol 19:151–157PubMedCrossRefGoogle Scholar
  94. 94.
    Dardenne M, Pléau JM, Nabarra B et al (1982) Contribution of zinc and other metals to the biological activity of the serum thymic factor. Proc Natl Acad Sci USA 79:5370–5373PubMedCrossRefGoogle Scholar
  95. 95.
    Goso C, Frasca D, Doria G (1992) Effect of synthetic thymic humoral factor (THF-gamma 2) on T cell activities in immunodeficient ageing mice. Clin Exp Immunol 87:346–351PubMedCrossRefGoogle Scholar
  96. 96.
    Goldstein AL (2007) History of the discovery of the thymosins. Ann N Y Acad Sci 1112:1–13PubMedCrossRefGoogle Scholar
  97. 97.
    Goldstein AL, Badamchian M (2004) Thymosins: Chemistry and biological properties in health and disease. Expert Opin Biol Ther 4:559–573PubMedCrossRefGoogle Scholar
  98. 98.
    Hannappel E, Huff T (2003) The thymosins. Prothymosin alpha, parathymosin, and beta-thymosins: Structure and function. Vitam Horm 66:257–296PubMedCrossRefGoogle Scholar
  99. 99.
    Chen C, Li M, Yang H et al (2005) Roles of thymosins in cancers and other organ systems. World J Surg 29:264–270PubMedCrossRefGoogle Scholar
  100. 100.
    Hirokawa K, McClure JE, Goldstein AL (1982) Agerelated changes in localization of thymosin in the human thymus. Thymus 4:19–29PubMedGoogle Scholar
  101. 101.
    Naylor PH, Friedman-Kien A, Hersh E et al (1986) Thymosin alpha 1 and thymosin beta 4 in serum: Comparison of normal, cord, homosexual and AIDS serum. Int J Immunopharmacol 8:667–676PubMedCrossRefGoogle Scholar
  102. 102.
    Weller FE, Shah U, Cummings GD et al (1992) Serum levels of immunoreactive thymosin alpha 1 and thymosin beta 4 in large cohorts of healthy adults. Thymus 19:45–52PubMedGoogle Scholar
  103. 103.
    Hsia J, Sarin N, Oliver JH, Goldstein AL (1989) Aspirin and thymosin increase interleukin-2 and interferon-gamma production by human peripheral blood lymphocytes. Immunopharmacology 17:167–173PubMedCrossRefGoogle Scholar
  104. 104.
    Huang KY, Kind PD, Jagoda EM, Goldstein AL (1981) Thymosin treatment modulates production of interferon. J Interferon Res 1:411–420PubMedGoogle Scholar
  105. 105.
    Leichtling KD, Serrate SA, Sztein MB (1990) Thymosin alpha 1 modulates the expression of high affinity interleukin-2 receptors on normal human lymphocytes. Int J Immunopharmacol 12:19–29PubMedCrossRefGoogle Scholar
  106. 106.
    Serrate SA, Schulof RS, Leondaridis L et al (1987) Modulation of human natural killer cell cytotoxic activity, lymphokine production, and interleukin 2 receptor expression by thymic hormones. J Immunol 139:2338–2343PubMedGoogle Scholar
  107. 107.
    Svedersky LP, Hui A, May L et al (1982) Induction and augmentation of mitogen-induced immune interferon production in human peripheral blood lymphocytes by N alpha-desacetylthymosin alpha 1. Eur J Immunol 12:244–247PubMedCrossRefGoogle Scholar
  108. 108.
    Sztein MB, Serrate SA (1989) Characterization of the immunoregulatory properties of thymosin alpha 1 on interleukin-2 production and interleukin-2 receptor expression in normal human lymphocytes. Int J Immunopharmacol 11:789–800PubMedCrossRefGoogle Scholar
  109. 109.
    Thurman GB, Seals C, Low TL, Goldstein AL (1984) Restorative effects of thymosin polypeptides on purified protein derivative — Dependent migration inhibition factor production by the peripheral blood lymphocytes of adult thymectomized guinea pigs. J Biol Response Mod 3:160–173PubMedGoogle Scholar
  110. 110.
    Zatz MM, McClure JE, Goldstein AL et al (1984) Thymosin increases production of T-cell growth factor by normal human peripheral blood lymphocytes. Proc Natl Acad Sci USA 81:2882–2885PubMedCrossRefGoogle Scholar
  111. 111.
    Ahmed A, Wong DM, Thurman GB et al (1979) T-lymphocyte maturation: Cell surface markers and immune function induced by T-lymphocyte cell-free products and thymosin polypeptides. Ann N Y Acad Sci 332:81–94PubMedCrossRefGoogle Scholar
  112. 112.
    Baxevanis CN, Reclos GJ, Perez S et al (1987) Immunoregulatory effects of fraction 5 thymus peptides. I. Thymosin alpha 1 enhances while thymosin beta 4 suppresses the human autologous and allogeneic mixed lymphocyte reaction. Immunopharmacology 13:133–141PubMedCrossRefGoogle Scholar
  113. 113.
    Frasca D, Adorini L, Doria G (1987) Enhanced frequency of mitogen-responsive T cell precursors in old mice injected with thymosin alpha 1. Eur J Immunol 17:727–730PubMedCrossRefGoogle Scholar
  114. 114.
    Schulof RS, Naylor PH, Sztein MB, Goldstein AL (1987) Thymic physiology and biochemistry. Adv Clin Chem 26:203–292PubMedCrossRefGoogle Scholar
  115. 115.
    Sztein MB, Goldstein AL (1986) Thymic hormones — A clinical update. Springer Semin Immunopathol 9:1–18PubMedCrossRefGoogle Scholar
  116. 116.
    Low TL, Hu SK, Goldstein AL (1981) Complete amino acid sequence of bovine thymosin beta 4: a thymic hormone that induces terminal deoxynucleotidyl transferase activity in thymocyte populations. Proc Natl Acad Sci USA 78:1162–1166PubMedCrossRefGoogle Scholar
  117. 117.
    Hall NR, McGillis JP, Spangelo BL, Goldstein AL (1985) Evidence that thymosins and other biologic response modifiers can function as neuroactive immunotransmitters. J Immunol 135:806s–811sPubMedGoogle Scholar
  118. 118.
    Rebar RW, Miyake A, Low TL, Goldstein AL (1981) Thymosin stimulates secretion of luteinizing hormone-releasing factor. Science 214:669–671PubMedCrossRefGoogle Scholar
  119. 119.
    Kokkinopoulos D, Perez S, Papamichail M (1985) Thymosin beta 4 induced phenotypic changes in Molt-4 leukemic cell line. Blut 50:341–348PubMedCrossRefGoogle Scholar
  120. 120.
    Fan YZ, Chang H, Yu Y et al (2006) Thymopentin (TP5), an immunomodulatory peptide, suppresses proliferation and induces differentiation in HL-60 cells. Biochim Biophys Acta 1763:1059–1066PubMedCrossRefGoogle Scholar
  121. 121.
    Liu Z, Zheng X, Wang J, Wang E (2007) Molecular Analysis of Thymopentin Binding to HLA-DR Molecules. PLoS ONE 2: e1348PubMedCrossRefGoogle Scholar
  122. 122.
    Goldstein G, Audhya TK (1985) Thymopoietin to thymopentin: Experimental studies. Surv Immunol Res 4Suppl 1:1–10PubMedGoogle Scholar
  123. 123.
    Gastinel LN, Dardenne M, Pleau JM, Bach JF (1984) Studies on the zinc binding site to the serum thymic factor. Biochim Biophys Acta 797:147–155PubMedGoogle Scholar
  124. 124.
    Savino W, Dardenne M, Bach JF (1983) Thymic hormone containing cells. III. Evidence for a feed-back regulation of the secretion of the serum thymic factor (FTS) by thymic epithelial cells. Clin Exp Immunol 52:7–12PubMedGoogle Scholar
  125. 125.
    Cohen S, Berrih S, Dardenne M, Bach JF (1986) Feedback regulation of the secretion of a thymic hormone (thymulin) by human thymic epithelial cells in culture. Thymus 8:109–119PubMedGoogle Scholar
  126. 126.
    Timsit J, Savino W, Safieh B et al (1992) Growth hormone and insulin-like growth factor-I stimulate hormonal function and proliferation of thymic epithelial cells. J Clin Endocrinol Metab 75:183–188PubMedCrossRefGoogle Scholar
  127. 127.
    Ban E, Gagnerault MC, Jammes H et al (1991) Specific binding sites for growth hormone in cultured mouse thymic epithelial cells. Life Sci 48:2141–2148PubMedCrossRefGoogle Scholar
  128. 128.
    Goya RG, Brown OA, Pleau JM, Dardenne M (2004) Thymulin and the neuroendocrine system. Peptides 25:139–142PubMedCrossRefGoogle Scholar
  129. 129.
    Kook AI, Trainin N (1974) Hormone-like activity of a thymus humoral factor on the induction of immune competence in lymphoid cells. J Exp Med 139:193–207PubMedCrossRefGoogle Scholar
  130. 130.
    Small M, Trainin N (1967) Increase in antibody-forming cells of neonatally thymectomized mice receiving calf thymus extract. Nature 216:377–379PubMedCrossRefGoogle Scholar
  131. 131.
    Bramucci M, Miano A, Quassinti L et al (2003) Degradation of thymic humoral factor gamma2 by human plasma: Involvement of angiotensin converting enzyme. Regul Pept 111:199–205PubMedCrossRefGoogle Scholar
  132. 132.
    Burstein Y, Buchner V, Pecht M, Trainin N (1988) Thymic humoral factor gamma 2: purification and amino acid sequence of an immunoregulatory peptide from calf thymus. Biochemistry 27:4066–4071PubMedCrossRefGoogle Scholar
  133. 133.
    Rotter V, Trainin N (1975) Increased mitogenic reactivity of normal spleen cells to T lectins induced by thymus humoral factor (THF). Cell Immunol 16:413–421PubMedCrossRefGoogle Scholar
  134. 134.
    Umiel T, Trainin N (1975) Increased reactivity of responding cells in the mixed lymphocyte reaction by a thymic humoral factor. Eur J Immunol 5:85–88PubMedCrossRefGoogle Scholar
  135. 135.
    Trainin N, Small M (1970) Studies on some physicochemical properties of a thymus humoral factor conferring immunocompetence on lymphoid cells. J Exp Med 132:885–897PubMedCrossRefGoogle Scholar
  136. 136.
    Umiel T, Altman A, Trainin N (1976) Augmentation of cell mediated lysis (CML) by THF. Adv Exp Med Biol 66:639–643PubMedGoogle Scholar
  137. 137.
    Umiel T, Pecht M, Trainin N (1984) THF, a thymic hormone, promotes interleukin-2 production in intact and thymus-deprived mice. J Biol Response Mod 3:423–434PubMedGoogle Scholar
  138. 138.
    Handzel ZT, Burstein Y, Buchner V et al (1990) Immunomodulation of T cell deficiency in humans by thymic humoral factor: From crude extract to synthetic thymic humoral factor-gamma 2. J Biol Response Mod 9:269–278PubMedGoogle Scholar
  139. 139.
    Rashid G, Ophir R, Pecht M et al (1996) Inhibition of murine Lewis lung carcinoma metastases by combined chemotherapy and intranasal THF-gamma 2 immunotherapy. J Immunother Emphasis Tumor Immunol 19:324–333PubMedGoogle Scholar
  140. 140.
    Ophir R, Pecht M, Keisari Y et al (1996) Thymic humoral factor-gamma 2 (THF-gamma 2) immunotherapy reduces the metastatic load and restores immunocompetence in 3LL tumor-bearing mice receiving anticancer chemotherapy. Immunopharmacol Immuno toxicol 18:209–236Google Scholar
  141. 141.
    Besedovsky HO, del Rey A (1996) Immune-neuro-endocrine interactions: Facts and hypotheses. Endocr Rev 17:64–102PubMedGoogle Scholar
  142. 142.
    Blalock JE (1994) The syntax of immune-neuroendocrine communication. Immunol Today 15:504–511PubMedCrossRefGoogle Scholar
  143. 143.
    Madden KS, Felten DL (1995) Experimental basis for neural-immune interactions. Physiol Rev 75:77–106PubMedGoogle Scholar
  144. 144.
    Savino W, Dardenne M (1995) Immune-neuroendocrine interactions. Immunol Today 16:318–322PubMedCrossRefGoogle Scholar
  145. 145.
    Min H, Montecino-Rodriguez E, Dorshkind K (2006) Reassessing the role of growth hormone and sex steroids in thymic involution. Clin Immunol 118:117–123PubMedCrossRefGoogle Scholar
  146. 146.
    Viganò A, Saresella M, Trabattoni D et al (2004) Growth hormone in T-lymphocyte thymic and postthymic development: A study in HIV-infected children. J Pediatr 145:542–548PubMedCrossRefGoogle Scholar
  147. 147.
    Koutkia P, Eaton K, You SM et al (2006) Growth hormone secretion among HIV infected patients: Effects of gender, race and fat distribution. Aids 20:855–862PubMedCrossRefGoogle Scholar
  148. 148.
    Goldberg GL, Zakrzewski JL, Perales MA, van den Brink MR (2007) Clinical strategies to enhance T cell reconstitution. Semin Immunol 19:289–296PubMedCrossRefGoogle Scholar
  149. 149.
    Savino W, Dardenne M (2000) Neuroendocrine control of thymus physiology. Endocr Rev 21:412–443PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Italia 2008

Authors and Affiliations

  • Milena Nasi
    • 1
  • Marcello Pinti
    • 1
  • Leonarda Troiano
    • 1
  • Andrea Cossarizza
    • 1
  1. 1.Department of Biomedical SciencesUniversity of Modena and Reggio EmiliaModenaItaly

Personalised recommendations