Kinetics of Negative and Positive Selection in the Thymus

  • Pawel Kisielow
  • Harald von Boehmer
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 292)


Recent experiments show that CD4+8+ thymocytes represent the critical stage in T cell development at which the specificity of randomly generated αβ T cell receptors is screened. These cells are deleted when the receptor binds to the MHC molecule plus specific peptide presented by bone marrow derived cells but are rescued from cell death and induced to mature if the receptor binds to the MHC molecule on thymic epithelium in the absence of the specific peptide. Different tolerogens delete CD4+8+ thymocytes earlier or later during their lifespan and negative selection can occur prior to positive selection. The specificity of the αβ T cell receptor for either class I or class II thymic MHC molecules determines the CD4-8+ and CD4+8- phenotype of mature T cells.


Transgenic Mouse Cell Receptor Negative Selection Specific Peptide Thymic Epithelium 
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  1. 1.
    H. M. Grey, A. Sette, and S. Buus, How T cells see antigen, Sci. Amer. 261:38 (1989).CrossRefGoogle Scholar
  2. 2.
    Z. Dembic, W. Haas, S. Weiss, J. McCubrey, H. Kiefer, H. von Boehmer, and M. Steinmetz, Transfer of specificity by murine a and β; T cell receptor genes, Nature 320:232 (1986).PubMedCrossRefGoogle Scholar
  3. 3.
    P. Kisielow, J. A. Hirst, H. Shiku, P. Beverley, M. K. Hoffman, E. A. Boyse, H. F. Ottegen, Ly antigens as markers for functionally distinct subpopulations of thymus derived lymphocytes of the mouse, Nature 253:219 (1975).PubMedCrossRefGoogle Scholar
  4. 4.
    D. P. Dialynas, Z. S. Quan, K. A. Wall, A. Pierres, J. Quintans, M. R. Loken, M. Pierres, and F. Fitch, Characterization of the murine antigenic determinent, designated L3T4a, recognized by monoclonal antibody GDI.5: similarity of L3T4 to the human Leu/T4 molecule, J. Immunol. 131:2445 (1983).PubMedGoogle Scholar
  5. 5.
    C. Doyle, J. L. Strominger, Interaction between CD4 and class II MHC molecules mediates cell adhesion, Nature 330:256 (1987).PubMedCrossRefGoogle Scholar
  6. 6.
    A. Norment, R. Salter, P. Parham, V. Engelhardt, and D. Littman, Cell-cell adhesion mediated by CD8 and MHC class I molecules, Nature 336:79 (1988).PubMedCrossRefGoogle Scholar
  7. 7.
    S. Swain, T cell subsets and the recognition of MHC class, Immunol. Rev. 74:129 (1983).PubMedCrossRefGoogle Scholar
  8. 8.
    E. L. Reinherz, S. F. Schlossman, The differentiation and functions of human T cells, Cell 19:821 (1980).PubMedCrossRefGoogle Scholar
  9. 9.
    F. Emmerich, V. Strittmatter, and K. Eichmann, Synergism in the activation of human CD8 T cells by cross-linking the T cell receptor complex with the CD8 differen-tiation antigen, Proc. Natl. Acad. Sci. USA 83:8298 (1986).CrossRefGoogle Scholar
  10. 10.
    J. Gabert, C. Langlet, R. Zamoyska, J. R. Parnes, A. Schmitt-Verhulst, and B. Malissen, Reconstitution of MHC class I specificity by T cell receptor and by Lut-2 gene transfer, Cell 50:545 (1987).PubMedCrossRefGoogle Scholar
  11. 11.
    P. Kisielow, W. Leiserson, and H. von Boehmer, Differentiation of thymocytes in fetal organ culture: analysis of phenotypic changes accompanying the appearance of cytolytic and interleukin 2 producing cells, J. Immunol. 133: 1117–1123 (1984).PubMedGoogle Scholar
  12. 12.
    R. Kingston, E. J. Jenkinson, and J. J. T. Owen, A single stem cell can recolonize an embryonic thymus producing phenotypically distinct T cell populations, Nature 317:811 (1985).PubMedCrossRefGoogle Scholar
  13. 13.
    H. R. Snodgrass, P. Kisielow, M. Kiefer, M. Steinmetz, and H. von Boehmer, Ontogeny of the T cell antigen receptor within the thymus, Nature 313:592 (1985).PubMedCrossRefGoogle Scholar
  14. 14.
    A. Crisanti, A. colontani, H. R. Snodgrass, and H. von Boehmer, Expression of T cell receptors by thymocytes: in situ staining and biochemical analysis, EMBO J. 5:2837 (1986).Google Scholar
  15. 15.
    D. H. Raulet, R. D. Garman, H. Saito, and S. Tonegawa, Developmental regulation of T cell receptor gene expression, Nature 314:103 (1985).PubMedCrossRefGoogle Scholar
  16. 16.
    H. R. Snodgrass, Z. Dembic, M. Steinmetz, and H. von Boehmer, Expression of T cell antigen receptor genes during fetal development in the thymus, Nature 315:232 (1985).PubMedCrossRefGoogle Scholar
  17. 17.
    N. Roehm, L. Herron, J. Cambier, D. DiGusto, K. Haskins, J. W. Kappler, and P. Marrack, The major histocompatibility complex restricted antigen receptor on T cells. Distribution on thymus and peripheral T cells. Cell 38:577 (1984).PubMedCrossRefGoogle Scholar
  18. 18.
    R. T. Kubo, W. Born, J. W. Kappler, P. Marrack, and M. Pigeon, Characterization of a monoclonal antibody which detects all murine a;T cell receptors, J. Immunol. 142: 2736–2742 (1989).PubMedGoogle Scholar
  19. 19.
    D. McPhee, J. Pye, and K. Shortman, The differentiation of T lymphocytes. V. Evidence for intrathymic death of most thymocytes, Thymus 1:151 (1979).PubMedGoogle Scholar
  20. 20.
    W. Born, M. McDuffie, N. Roehm, E. Kushnir, J. White, D. Thorpe, J. P. Stefano, J. W. Kappler, and P. Marrack, Expression and role of the T cell receptor in early thymocyte differentiation in vitro. J. Immunol 138:999 (1987).PubMedGoogle Scholar
  21. 21.
    M. McDuffie, W. Born, P. Marrack, and J. W. Kappler, The role of the T cell receptor in thymocyte maturation: effects in vivo of antireceptor antibody. Proc. Natl. Acad. Sci. USA 83:8720 (1986).CrossRefGoogle Scholar
  22. 22.
    B. J. Fowlkes, R. H. Schwartz, and D. M. Pardoll, Deletion of self-reactive thymocytes occurs at a CD4+8+ precursor stage, Nature 334:620 (1988).PubMedCrossRefGoogle Scholar
  23. 23.
    H. R. MacDonald, H. Hengarner, and M. Pedrazzini, Intrathymic deletion of self-reactive cells prevented by neonatal anti-CD4 antibody treatment, Nature 335: 174 (1988).PubMedCrossRefGoogle Scholar
  24. 24.
    J. C. Zuniga-Pflucker, S. A. McCarthy, M. Weston, D. L. Longo, A. Singer, and A. M. Kruisbeek, Role of CD4 in thymocyte selection and maturation, J. Exp. Med. 169: 2085 (1989).PubMedCrossRefGoogle Scholar
  25. 25.
    J. C. Zuniga-Pflucker, D. L. Long, and A. M. Kruisbeek, Positive selection of CD4-/CD8+ T cells in the thymus of normal mice, Nature 338:76 (1988).CrossRefGoogle Scholar
  26. 26.
    S. Marusic-Galesic, D. L. Longo, and A. M. Kruisbeek, Preferential differentiation of T cell receptor specificities based on the MHC glycoproteins encountered during development: evidence for positive selection, J. Exp. Med. 169:1619–1628 (1989).PubMedCrossRefGoogle Scholar
  27. 27.
    A. M. Kruisbeek, J. J. Mond, B. J. Fowlkes, J. A. Carmen, S. Bridges, and D. L. Longo, Absence of the Lyt2-, L3T4+ lineage of T cells in mice treated neonatally with anti-I-A correlates with the absence of intrathymic I-A bearing antigen-presenting cell function, J. Exp. Med. 161:1029 (1985).PubMedCrossRefGoogle Scholar
  28. 28.
    P. Marrack, E. Kushnir, W. Born, M. McDuffie, and J. W. Kappler, The development of helper T cell precursors in mouse thymus, J. Immunol. 140:2508 (1988).PubMedGoogle Scholar
  29. 29.
    J. W. Kappler, U. Staerz, J. White, and P. Marrack, Self-tolerance eliminates T cells specific for Mis-modified products of the major histocompatibility complex, Nature 332:35 (1988).PubMedCrossRefGoogle Scholar
  30. 30.
    H. R. MacDonald, R. Schneider, K. Lees, R. C. Howe, H. Acha-Orbea, H. Festenstein, R. M. Zinkernagel, and H. Hengartner, T cell receptor V-beta use predicts reactivity and tolerance to Mls(a)-encoded antigens, Nature 332:40 (1988).PubMedCrossRefGoogle Scholar
  31. 31.
    J. White, A. Herman, A. M. Pullen, R. T. Kubo, J. W. Kappler, and P. Marrack, The V; specific superantigen Staphylococcal enterotoxin B: stimulation of mature T cells and clonal deletion in neonatal mice, Cell 56:27 (1989).PubMedCrossRefGoogle Scholar
  32. 32.
    W. vanEwijk, Y. Ron, J. Monaco, J. W. Kappler, P. Marrack, M. LeMeur, P. Gerlinger, B. Durand, C. Benoist, and D. Mathis, Compartmentalization of MHC class II gene expression in transgenic mice, Cell 53:357 (1988).PubMedCrossRefGoogle Scholar
  33. 33.
    C. Benoist and D. Mathis, Positive selection of the T cell repertoire: Where and when does it occur? Cell 58: 1027 (1989).PubMedCrossRefGoogle Scholar
  34. 34.
    J. Bill and E. Palmer, Positive selection of CD4+ T cells mediated by MHC class II-bearing stromal cell in the thymus, Nature 341:649 (1989).PubMedCrossRefGoogle Scholar
  35. 35.
    Y. Uematsu, S. Ryser, Z. Dembic, P. Borgulya, P. Krimpenfort, A. Berns, H. von Boehmer, and M. Steinmetz, In transgenic mice the introduced functional T cell receptor p gene prevents expression of endogenous ; genes, Cell 52:831 (1988).PubMedCrossRefGoogle Scholar
  36. 36.
    L. J. Berg, B. Fazekas de St. Groth, A. M. Pullen, and M. M. Davis, Phenotypic differences between αβ; and T cell receptor transgenic mice undergoing negative selection, Nature 340:559 (1989).PubMedCrossRefGoogle Scholar
  37. 37.
    H. Pircher, T. K. Mak, R. Lang, W. Ballhausen, E. Ruedi, H. Hengartner, R. M. Zinkernagel, and K. Burki, T cell tolerance to Mlsa encoded antigens in T cell receptor Vβ;8.1 chain transgenic mice, EMBO J. 8:719 (1989).PubMedGoogle Scholar
  38. 38.
    P. Kisielow, H. Bluthmann, U. Staerz, M. Steinmetz, and H. von Boehmer, Tolerance in T-cell receptor transgenic mice involves deletion of nonmature CD4+8+ thymocytes, Nature 333:742 (1988).PubMedCrossRefGoogle Scholar
  39. 39.
    H. Bluthman, P. Kisielow, Y. Uematsu, M. Mallissen, P. Krimpenfort, A, Berns, H. von Boehmer, and M. Steinmetz, T cell specific deletion of T cell receptor trans-genes allows functional rearrangement of endogenous a and ; genes, Nature 334:156 (1988).CrossRefGoogle Scholar
  40. 40.
    W. C. Sha, C. A. Nelson, R. D. Newberry, D. M, Kranz, J, H. Russel, and D. Y. Loh, Selective expression of an antigen receptor on CD8-bearing T lymphocytes in transgenic mice, Nature 335:271 (1988).PubMedCrossRefGoogle Scholar
  41. 41.
    L. J. Berg, A. M. Pullen, B. Fazekas de St. Groth, D. Mathis, C. Benoist, and M. M. Davis, Antigen/MHC-specific T cells are preferentially exported from the thymus in the presence of their MHC ligand, Cell 58:1035 (1989).PubMedCrossRefGoogle Scholar
  42. 42.
    J. Kaye, M. L. Hsu, M, E. Sauron, J. C. Jameson, R. J. Gascoigne, and S. M. Hedrick, Selective development of CD4 T cell in transgenic mice expressing a class II MHC-restricted antigen receptor, Nature 341:746 (1989).PubMedCrossRefGoogle Scholar
  43. 43.
    H. von Boehmer, H. S. Teh, and P. Kisielow, Thymus selects the useful, neglects the useless and destroys the harmful, Immunol. Today 10:57 (1989).Google Scholar
  44. 44.
    H. von Boehmer, Developmental biology of T cells in T-cell receptor transgenic mice, Ann. Rev. Immunol. (1990, in press).Google Scholar
  45. 45.
    J. Lederberg, Genes and antibodies, Science 129: 1649 (1959).PubMedCrossRefGoogle Scholar
  46. 46.
    H. von Boehmer, The selection of the αβ; heterodimeric T cell receptor for antigen, Immunol. Today 7:333 (1986).Google Scholar
  47. 47.
    P. Marrack and J. W. Kappler, The T cell receptor, Science 238:1073 (1987).PubMedCrossRefGoogle Scholar
  48. 48.
    P. Matzinger, R. Zamoyska, and H. Waldmann, Self-tolerance is H-2 restricted, Nature 308:738 (1984).PubMedCrossRefGoogle Scholar
  49. 49.
    H. G. Rammensee and M. Bevan, Evidence from in vitro studies that tolerance to self is MHC restricted, Nature 308:741 (1984).PubMedCrossRefGoogle Scholar
  50. 50.
    M. M. Davis and P. Bjorkman, T cell antigen receptor genes and T cell recognition, Nature 334:395 (1988).PubMedCrossRefGoogle Scholar
  51. 51.
    P. Bjorkman, M. A. Saper, B. Samaoui, W. S. Bennett, J. L. Strominger, and D. C. Wiley, Structure of the human class I histocompatibility antigen, HLA-A2, Nature 329:506 (1987).CrossRefGoogle Scholar
  52. 52.
    M. Bevan, In a radiation chimaera, host H-2 antigens determine immune responsiveness of donor cytotoxic cells, Nature 269:417 (1977).PubMedCrossRefGoogle Scholar
  53. 53.
    H. von Boehmer, W. Haas, and N. K. Jerne, Major histocompatibility complex-linked immune-responsiveness is acquired by lymphocytes of low responder mice differen-tiating in thymus of high-responder mice, Proc. Natl. Acad. Sci. USA 75:2439 (1978).CrossRefGoogle Scholar
  54. 54.
    R. M. Zinkernagel, G. Callahan, A. Althage, S. Cooper, P. Klein, and J. Klein, On the thymus in the differentiation of “H-2 self-recognition” by T cells: Evidence for dual recognition? J. Exp. Med. 147:882 (1978).PubMedCrossRefGoogle Scholar
  55. 55.
    D. Loh and J. Sprent, Identity of cells that imprint H-2 restricted T cell specificity in the thymus, Nature 319:672 (1986).CrossRefGoogle Scholar
  56. 56.
    H. S. Teh, H. Kishi, B. Scott, P. Borgulya, H. von Boehmer, and P. Kisielow, Early deletion and late positive selection of T cells expressing a male-specific receptor in T cell receptor transgenic mice, Developmental Immunol. (1990, in press).Google Scholar
  57. 57.
    H. von Boehmer, M. Bonneville, I. Ishida, S. Ryser, G. Lincoln, R. T. Smith, H. Kishi, B. Scott, P. Kisielow, and S. Tonegawa, Early expression of a T cell receptor βchain transgene suppresses rearrangement of the V4 gene segment, Proc. Natl. Acad. Sci. USA 85:9729 (1988).CrossRefGoogle Scholar
  58. 58.
    B. Scott, H. Bluthmann, H. S. Teh, and H. von Boehmer, The generation of mature T cells requires interaction of the ; T cell receptor with major histo-compatibility complex antigens and the ; T cell receptor determine the CD4/CD8 phenotype of T cells, Nature 335:229 (1988).PubMedCrossRefGoogle Scholar
  59. 59.
    H. S. Teh, P. Kisielow, B. Scott, H. Kishi, Y. Uematsu, H. Bluthmann, and H. von Boehmer, Thymic major histocompatibility complex antigens and the αβ; T cell receptor determine the CD4/CD8 phenotype of T cells, Nature 335:229 (1988).PubMedCrossRefGoogle Scholar
  60. 60.
    W. C. Sha, C. A. Nelson, R. D. Newberry, D. M. Kranz, J. H. Russell, and D. Y. Loh, Positive and negative selection of an antigen receptor on T cells in transgenic mice, Nature 336:73 (1988).PubMedCrossRefGoogle Scholar
  61. 61.
    P. Krimpenfort, B. J. Ossendorp, C. Melief, and A. Berns, T cell depletion in transgenic mice carrying a mutant gene for TCR-β;, Nature 341:742 (1989).PubMedCrossRefGoogle Scholar
  62. 62.
    J. W. Kappler, N. Roehm, and P. Marrack, T cell tolerance by clonal elimination in the thymus, Cell 49:273 (1987).PubMedCrossRefGoogle Scholar
  63. 63.
    T. H. Finkel, J. C. Cambier, R. T. Kubo, W. K. Born, P. Marrack, and J. W. Kappler, The thymus has two functionally distinct populations of immature aβ;+ cells: one population is deleted by ligation of αβ; TCR, Cell 58: 1047 (1989).PubMedCrossRefGoogle Scholar
  64. 64.
    P. Borgulya, H. Kishi, B. Scott, Y. Uematsu, A. Berns, and H. von Boehmer, Positive and negative selection of T cells: which comes first? (Submitted)Google Scholar
  65. 65.
    D. A. Ferrick, P. S. Ohashi, V. Wallace, M. Schilham, and T. W. Mak, Thymic ontogeny and selection of α, β, and ,T cells, Immunol. Today 10:403 (1989).CrossRefGoogle Scholar
  66. 66.
    W. van Ewijk, P. Kisielow, and H. von Boehmer, Immunohistology of T cell differentiation in the thymus of HY specific αβ;T cell receptor transgenic mice, Eur. J. Immunol. 20: 129 (1990).PubMedCrossRefGoogle Scholar
  67. 67.
    H. S. Teh, H. Kishi, B. Scott, and H. von Boehmer, Deletion of autospecific T cells in T cell receptor transgenic mice spares cells with normal TCR levels and low levels of CD8 molecules, J. Exp. Med. 169:795 (1989).PubMedCrossRefGoogle Scholar
  68. 68.
    C. Penit and F. Vasseur, Sequential events in thymocyte differentiation and thymus regeneration revealed by a combination of bromodeoxyuridine DNA labelling and antimitotic drug treatments, J. Immunol. 140:3315 (1989).Google Scholar
  69. 69.
    J. Nicolic-Zugic and M. Bevan, Thymocytes expressing CD8 differentiate into CD4+ cells following intrathymic injection, Proc. Natl. Acad. Sci. USA 85:8663 (1988).Google Scholar
  70. 70.
    P. Kisielow, H. S. Teh, H. Bluthmann, and H. von Boehmer, Positive selection of antigen-specific T cells in thymus by restricting MHC molecules, Nature 335:730 (1988).PubMedCrossRefGoogle Scholar
  71. 71.
    M. Blackman, P. Marrack, and J. Kappler, Influence of the MHC on positive thymic selection of V/317+ T cells, Science 244:214 (1989).PubMedCrossRefGoogle Scholar
  72. 72.
    H. R. MacDonald, R. K. Lees, R. Schneider, R. Zinkernagel, and H. Hengartner, Positive selection of CD4+ thymocytes controlled by MHC class II gene products, Nature 336:471 (1988).PubMedCrossRefGoogle Scholar
  73. 73.
    A. Villette, J. C. Zuniga-Pflucker, J. B. Bolen, and A. M. Kruisbeek, Engagement of CD4 and CD8 expressed on immature thymocytes induces activation of intracellular tyrosine phosphorylation pathways, J. Exp. Med. 170:1671 (1989).CrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1991

Authors and Affiliations

  • Pawel Kisielow
    • 1
    • 2
  • Harald von Boehmer
    • 1
  1. 1.Basel Institute for ImmunologyBaselSwitzerland
  2. 2.Institute of Immunology and Experimental TherapyPolish Academy of SciencesWroclawPoland

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