The Molecular Basis of Thymocyte Positive Selection and CD4/CD8 Lineage Commitment

  • Cynthia J. Guidos
Part of the Contemporary Immunology book series (CONTIM)


It has been 20 years since it was first postulated that developing T-cells undergo a positive selection process that ensures that only those bearing self-MHC restricted TCRαβ mature and exit the thymus to form the peripheral T-cell pool (1,2). It is now clear that positive selection operates on a pool of immature TCRαβ+ thymocytes that express high levels of CD4 and CD8. These coreceptors recognize MHC Class II or Class I molecules, respectively, and function both to stabilize TCRαβ interactions with MHC/peptide ligands, as well to recruit the Lck protein tyrosine kinase to the TCRαβ/CD3 complex, thus facilitating TCR-mediated signal transduction. In response to low avidity interactions between TCRαβ and MHC/peptide ligands expressed in the thymic cortex, DP thymocytes bearing potentially useful, self MHC-restricted TCRαβ are positively selected to survive and to mature into MHC II-restricted CD4+ helper, or MHC I-restricted CD8+ cytotoxic T-cells. Thus, positively selected DP thymocytes are rescued from programmed cell death, the fate of most DP cells, and become committed to the CD4 or CD8 single positive (SP) lineage. However, high avidity TCR-ligand interactions preferentially mediate clonal deletion of potentially autoreactive precursors, usually before the DP→SP transition is complete.


Major Histocompatibility Complex Major Histocompatibility Complex Class Lineage Commitment Single Positive Thymic Epithelium 
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.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Fink, P. J. and Bevan, M. J. (1978) H-2 antigens of the thymus determine lymphocyte specificity. J. Exp. Med. 148, 766–775.PubMedCrossRefGoogle Scholar
  2. 2.
    Zinkernagel, R. M., Callahan, G. N., Althage, A., Cooper, S., Klein, P. A., and Klein, J. (1978) On the thymus in the differentiation of “H-2 self-recognition” by T-cells: Evidence for dual recognition? J. Exp. Med. 147, 882–896.PubMedCrossRefGoogle Scholar
  3. 3.
    Guidos, C. J. (1996) Positive selection of CD4+ and CD8+ T cells. Curr. Opin. Immunol. 8, 225–232.PubMedCrossRefGoogle Scholar
  4. 4.
    Groves, T., Parsons, M., Miyamoto, N., and Guidos, C. J. (1997) TCR engagement of CD4+CD8+ thymocytes in vitro induces early aspects of positive selection, but not apoptosis. J. Immunol. 158, 65–75.PubMedGoogle Scholar
  5. 5.
    Kearse, K., Takahama, Y., Punt, J., Sharrow, S., and Singer, A. (1995) Early molecular events induced by TCR signaling in immature CD4+CD8+ thymocytes. J. Exp. Med. 181, 193–202.PubMedCrossRefGoogle Scholar
  6. 6.
    Turka, L. A., Schatz, D. G., Oettinger, M. A., Chun, J., Gorka, C., Lee, K., McCormack, W. T., and Thompson, C. B. (1991) Thymocyte expression of RAG-1 and RAG-2: Termination by T cell receptor cross-linking. Science 253, 778–781.PubMedCrossRefGoogle Scholar
  7. 7.
    Fischer, K.-D., Zmuidzinas, A., Gardner, S., Barbacid, M., Bernstein, A., and Guidos, C. (1995) Defective T-cell receptor signaling and positive selection of Vav-deficient CD4+CD8+ thymocytes. Nature 374, 474–477.PubMedCrossRefGoogle Scholar
  8. 8.
    Groves, T., Smiley, P., Cooke, M. P., Forbush, K., Perlmutter, R. M., and Guidos, C. J. (1996) Fyn can partially substitute for Lck in T lymphocyte development. Immunity 5, 417–428.PubMedCrossRefGoogle Scholar
  9. 9.
    Petrie, H. T., Strasser, A., Harris, A. W., Hugo, P., and Shortman, K. (1993) CD4+8- and CD4–8+ mature thymocytes require different post-selection processing for final development. J. Immunol. 151, 1273–1279.PubMedGoogle Scholar
  10. 10.
    Wilkinson, R. W., Anderson, G., Owen, J. J. T., and Jenkinson, E. J. (1995) Positive selection of thymocytes involves sustained interactions with the thymic microenvironment. J. Immunol. 155, 5234–5240.PubMedGoogle Scholar
  11. 11.
    Punt, J. A., Suzuki, H., Granger, L. G., Sharrow, S. O., and Singer, A. (1996) Lineage commitment in the thymus: only the most differentiated (TCRh’bc1–2h’) subset of CD4+CD8+ thymocytes has selectively terminated CD4 or CD8 synthesis. J. Exp. Med. 184, 2091–2099.PubMedCrossRefGoogle Scholar
  12. 12.
    Guidos, C. J. and Weissman, I. L. (1993) Sequential occurrence of positive and negative selection during T lymphocyte maturation, in Molecular Mechanisms ofImmunological Self-Recognition ( Alt, F., and Vogel, H. J., eds.) Academic, San Diego, CA, 137–147.Google Scholar
  13. 13.
    Guidos, C. J., Weissman, I. L., and Adkins, B. (1989) Intrathymic maturation of murine T lymphocytes from CD8+ precursors. Proc. Natl. Acad. Sci. USA 86, 7542–7546.PubMedCrossRefGoogle Scholar
  14. 14.
    Guidos, C. J., Danska, J. S., Fathman, C. G., and Weissman, I. L. (1990) T cell receptor-mediated negative selection of autoreactive T lymphocyte precursors occurs after commitment to the CD4 or CD8 lineages. J. Exp. Med. 172, 835–845.Google Scholar
  15. 15.
    Bendelac, A., Matzinger, P., Seder, R. A., Paul, W. E., and Schwartz, R. H. (1992) Activation events during thymic selection. J. Exp. Med. 175, 731–742.PubMedCrossRefGoogle Scholar
  16. 16.
    van Meerwijk, J. P. M. and Germain, R. N. (1993) Development of mature CD8+ thymocytes: selection rather than instruction? Science 261, 911–915.Google Scholar
  17. 17.
    van Meerwijk, J. P. M., O’Connell, E. M., and Germain, R. N. (1995) Evidence for lineage commitment and initiation of positive selection by thymocytes with intermediate surface phenotypes. J. Immunol. 154, 6314–6323.Google Scholar
  18. 18.
    Benveniste, P., Knowles, G., and Cohen, A. (1996) CD8/CD4 lineage commitment occurs by an instructional/default process followed by positive selection. Eur. J. Immunol. 26, 461–471.PubMedCrossRefGoogle Scholar
  19. 19.
    Lucas, B., and Germain, R. N. (1996) Unexpectedly complex regulation ofCD4/CD8 coreceptor expression supports a revised model for CD4+CD8+ thymocyte differentiation. Immunity 5, 461–477.PubMedCrossRefGoogle Scholar
  20. 20.
    Lundberg, K., Heath, W., Köntgen, F., Carbone, F. R., and Shortman, K. (1995) Intermediate steps in positive selection: differentiation of CD4+8`°tTCR`nt thymocytes into CD4–8+TCRh` thymocytes. J. Exp. Med. 181, 1643–1651.PubMedCrossRefGoogle Scholar
  21. 21.
    Suzuki, H., Punt, J., Granger, L., and Singer, A. (1995) Asymmetric signaling requirements for thymocyte commitment to the CD4+ versus CD8+ T cell lineages: a new perspective on thymic commitment and selection. Immunity 2, 413–425.PubMedCrossRefGoogle Scholar
  22. 22.
    Swat, W., Ignatowicz, L., von Boehmer, H., and Kisielow, P. (1991) Clonal deletion of immature CD4+8+ thymocytes in suspension culture by extrathymic antigen-presenting cells. Nature 351, 150–153.PubMedCrossRefGoogle Scholar
  23. 23.
    Kersh, G. J., and Hedrick, S. M. (1995) Role of TCR specificity in CD4 versus CD8 lineage commitment. J. Immunol. 154, 1057–1068.PubMedGoogle Scholar
  24. 24.
    Akashi, K., and Weissman, I. L. (1996) The c-kit+ maturation pathway in mouse thymic T cell development, lineages and selection. Immunity 5, 147–161.PubMedCrossRefGoogle Scholar
  25. 25.
    Weiss, A., and Littman, D. R. (1994) Signal transduction by lymphocyte antigen receptors. Cell 76, 263–274.PubMedCrossRefGoogle Scholar
  26. 26.
    Zamoyska, R. (1994) The CD8 coreceptor revisited: one chain good, two chains better. Immunity 1, 243–246.PubMedCrossRefGoogle Scholar
  27. 27.
    Wiest, D. L., Yuan, L., Jefferson, J., Benveniste, P., Tsokos, M., Klausner, R. D., Glimcher, L. H., Samelson, E., and Singer, A. (1993) Regulation of T cell receptor expression in immature CD4+CD8+thymocytes by p56“ tyrosine kinase: Basis for differential signaling by CD4 and CD8 in immature thymocytes expressing both coreceptor molecules. J. Exp. Med. 178, 1701–1712.PubMedCrossRefGoogle Scholar
  28. 28.
    Itano, A., Salmon, P.,Kioussis, D., Tolaini, M., Corbella, P., and Robey, E. (1996) The cytoplasmic domain of CD4 promotes the development of CD4 lineage T cells. J. Exp. Med. 183, 731–741.PubMedCrossRefGoogle Scholar
  29. 29.
    Seong, R. H., Chamberlain, J. W., and Parnes, J. R. (1992) Signal for T-cell differentiation to a CD4 cell lineage is delivered by CD4 transmembrane region and/or cytoplasmic tail. Nature 356, 718–720.PubMedCrossRefGoogle Scholar
  30. 30.
    Borgulya, P., Kishi, H., Uematsu, Y., and von Boehmer, H. (1992) Exclusion and inclusion of a and ß T cell receptor alleles. Cell 69, 529–537.PubMedCrossRefGoogle Scholar
  31. 31.
    Petrie, H. T., Livak, F., Schatz, D. G., Strasser, A., Crispe, I. N., and Shortman, K. (1993) Multiple rearrangements in TCRa chain genes maximize the production of useful thymocytes. J. Exp. Med. 178, 615–622.PubMedCrossRefGoogle Scholar
  32. 32.
    Matechak, E. O., Killeen, N., Hedrick, S. M., and Fowlkes, B. J. (1996) MHC class II-specific T cells can develop in the CD8 lineage when CD4 is absent. Immunity 4, 337–347.PubMedCrossRefGoogle Scholar
  33. 33.
    Kirberg, J., Baron, A., Jakob, S., Rolink, A., Karjalainen, K., and von Boehmer, H. (1994) Thymic selection of CD8+ single positive cells with a class II major histocompatibility complex-restricted receptor. J. Exp. Med. 180, 25–34.PubMedCrossRefGoogle Scholar
  34. 34.
    Bendelac, A. (1995) Positive selection of mouse NK1+ T cells by CD1-expressing cortical thymocytes. J. Exp. Med. 182, 2091–2096.PubMedCrossRefGoogle Scholar
  35. 35.
    Bendelac, A., Killeen, N., Littman, D. R., and Schwartz, R. H. (1994) A subset of CD4+ thymocytes selected by MHC class I molecules. Science 263, 1774–1778.PubMedCrossRefGoogle Scholar
  36. 36.
    Coles, M. C. and Raulet, D. H. (1994) Class I dependence of the development of CD4+CD8NK1.1+ thymocytes. J. Exp. Med. 180, 395–399.PubMedCrossRefGoogle Scholar
  37. 37.
    Cosgrove, D., Gray, D., Dierich, A., Kaufman, J., Lemeur, M., Benoist, C., and Mathis, C. C. (1991) Mice lacking MHC class II molecules. Cell 66, 1051–1066.PubMedCrossRefGoogle Scholar
  38. 38.
    Bommhardt, U., Cole, M. S., Tso, J. Y., and Zamoyska, R. (1997) Signals through CD8 or CD4 can induce commitment to the CD4 lineage in the thymus. Eur. J. Immunol. 27, 1152–1163.PubMedCrossRefGoogle Scholar
  39. 39.
    Goldrath, A. W., Hogquist, K. A., and Bevan, M. J. (1997) CD8 lineage commitment in the absence of CD8. Immunity 6, 633–642.PubMedCrossRefGoogle Scholar
  40. 40.
    Sebzda, E., Choi, M., Fung-Leung, W. P., T. Mak, W., and Ohashi, P. S. (1997) Peptide-induced positive selection of TCR transgenic thymocytes in a coreceptor-independent manner. Immunity 6, 643–653.PubMedCrossRefGoogle Scholar
  41. 41.
    Chan, S. H., Cosgrove, D., Waltzinger, C., Benoist, C., and Mathis, D. (1993) Another view of the selective model of thymocyte selection. Cell 73, 225–236.PubMedCrossRefGoogle Scholar
  42. 42.
    Davis, C. B., Killeen, N., Crooks, M. E. C., Raulet, D., and Littman, D. R. (1993) Evidence for a stochastic mechanism in the differentiation of mature subsets of T lymphocytes. Cell 73, 237–247.PubMedCrossRefGoogle Scholar
  43. 43.
    Cibotti, R., Punt, J. A., Dash, K. S., Sharrow, S. O., and Singer, A. (1997) Surface molecules that drive T cell development in vitro in the absence of thymic epithelium and in the absence of lineage-specific signals. Immunity 6, 245–255.PubMedCrossRefGoogle Scholar
  44. 44.
    Suzuki, H., Shinkai, Y., Granger, L. G., Alt, F. W., Love, P. E., and Singer, A. (1997) Commitment of immature CD4+CD8+ thymocytes to the CD4 lineage requires CD3 signaling but does not require expression of clonotypic T cell receptor (TCR) chains. J. Exp. Med. 186, 17–23.PubMedCrossRefGoogle Scholar
  45. 45.
    Crump, A. L., Grusby M. J., Glimcher, L. H., and Cantor, H. (1993) Thymocyte development in major histocompatibility complex-deficient mice: Evidence for stochastic commitment to the CD4 and CD8 lineages. Proc. Natl. Acad. Sci. USA 90, 10739–10743.PubMedCrossRefGoogle Scholar
  46. 46.
    Takahama, Y., Suzuki, H., Katz, K. S., Grusby, M. J., and Singer, A. (1994) Positive selection of CD4+ T cells by TCR ligation without aggregation even in the absence of MHC. Nature 371, 67–70.PubMedCrossRefGoogle Scholar
  47. 47.
    Zerrahn, J., Held, W., and Raulet, D. H. (1997) The MHC reactivity of the T cell repertoire prior to positive and negative selection. Cell 88, 627–636.PubMedCrossRefGoogle Scholar
  48. 48.
    Poirier, G., Lo, D., Reilly, C. R., and Kaye, J. (1994) Discrimination between thymic epithelial cells and peripheral antigen-presenting cells in the induction of immature T cell differentiation. Immunity 1, 385–391.PubMedCrossRefGoogle Scholar
  49. 49.
    Anderson, G., Jenkinson, E. J., Moore, N. C., and Owen, J. J. T. (1993) MHC class II-positive epithelium and mesenchyme cells are both required for T-cell development in the thymus. Nature 362, 70–73.PubMedCrossRefGoogle Scholar
  50. 50.
    Anderson, G., Owen, J. J. T., Moore, N. C., and Jenkinson, E. J. (1994) Thymic epithelial cells provide unique signals for positive selection of CD4+CD8+ thymocytes in vitro. J. Exp. Med. 179, 2027–2031.PubMedCrossRefGoogle Scholar
  51. 51.
    Ernst, B. B., Surh, C. D., and Sprent, J. (1996) Bone marrow-derived cells fail to induce positive selection in thymus reaggregation cultures. J. Exp. Med. 183, 1235–1240.PubMedCrossRefGoogle Scholar
  52. 52.
    Tanaka, Y., Williams, O., Tarazona, R., Wack, A., Norton, T., and Kioussis, D. (1996) In vitro positive selection of aß TCR transgenic thymocytes by a conditionally immortalized cortical epithelial clone. Int. Immunol. 9, 381–393.CrossRefGoogle Scholar
  53. 53.
    Muller, K. P. and Kyewski, B. A. (1993) T cell receptor targeting to thymic cortical epithelial cells in vivo induces survival, activation and differentiation of immature thymocytes. Eur. J. Immunol. 23, 1661–1670.PubMedCrossRefGoogle Scholar
  54. 54.
    Muller, K. P. and Kyewski, B. A. (1995) Intrathymic T cell receptor (TCR) targeting in mice lacking CD4 or major histocompatibility complex (MHC) class II, rescue of CD4 T cell lineage without co-engagement of TCR/CD4 by MHC class II. Eur. J. Immunol. 25, 896–902.PubMedCrossRefGoogle Scholar
  55. 55.
    Pawlowski, T., Elliott, J. D., Loh, D. Y., and Staerz, U. D. (1993) Positive selection of T lymphocytes on fibroblasts. Nature 364, 642–645.PubMedCrossRefGoogle Scholar
  56. 56.
    Bailey, A. M., and Posakony, J. W. (1995) Suppressor of hairless directly activates transcription of enhancer of split complex genes in response to Notch receptor activity. Genes Dey. 9, 2609–2622.CrossRefGoogle Scholar
  57. 57.
    Fortini, M. E. and Artavanis-Tsakonas, S. (1994) The suppressor of hairless protein participates in Notch receptor signaling. Cell 79, 273–282.PubMedCrossRefGoogle Scholar
  58. 58.
    Hsieh, J. J., Henkel, T., Salmon, P., Robey, E., Peterson, M. G., and Hayward, S. D. (1996) Truncated mammalian Notch 1 activates CBF 1 /RBPJk-repressed genes by a mechanism resembling that of Epstein-Barr virus EBNA2. Mol. Cell. Biol. 16, 952–959.PubMedGoogle Scholar
  59. 59.
    Ishibashi, M., Ang, S. L., Shiota, K., Nakanishi, S., Kageyama, R., and Guillemot, F. (1995) Targeted disruption of mammalian hairy and Enhancer of split homolog-1(HES-1) leads to up-regulation of neural helix-loop-helix factors, premature neurogenesis, and severe neural tube defects. Genes Dey. 9, 3136–3148.CrossRefGoogle Scholar
  60. 60.
    Jarriault, S., Brou, C., Logeat, F., Schroeter, E. H., Kopan, R., and Israel, A. (1995) Signalling downstream of activated mammalian Notch. Nature 377, 355–358.PubMedCrossRefGoogle Scholar
  61. 61.
    Tomita, K., Ishibashi, M., Nakahara, K., Ang, S. L., Nakanishi, S., Guillemot, F., and Kageyama, R. (1996) Mammalian hairy and Enhancer of split homolog 1 regulates differentiation of retinal neurons and is essential for eye morphogenesis. Neuron 16, 723–734.PubMedCrossRefGoogle Scholar
  62. 62.
    Robey, E., Chang, D., Itano, A., Cado, D., Alexander, H., Lans, D., Weinmaster, G., and Salmon, P. (1996) An activated form of Notch influences the choice between CD4 and CD8 T cell lineages. Cell 87, 483–492.PubMedCrossRefGoogle Scholar
  63. 63.
    Hasserjian, R. P., Aster, J. C., Davi, F., Weinberg, D. S., and Sklar, J. (1996) Modulated expression of Notchl during thymocyte development. Blood 88, 970–976.PubMedGoogle Scholar
  64. 64.
    Artavanis-Tsakonas, S., Matsuno, K., and Fortini, M. E. (1995) Notch signaling. Science 268, 225–232.PubMedCrossRefGoogle Scholar
  65. 65.
    Ellisen, L. W., Bird, J., West, D. C., Soreng, A. L., Reynolds, T. C., Smith, S. D., and Sklar, J. (1991) TAN-1, the human homolog of the Drosophila Notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms. Cell 66, 649–661.PubMedCrossRefGoogle Scholar
  66. 66.
    Aster, J. C., Robertson, E. S., Hasserjian, R. P., Turner, J. R., Kieff, E., and Sklar, J. (1997) Oncogenic forms of NOTCHI lacking either the primary binding site for RBP-Jic or nuclear localization sequences retain the ability to associate with RBP-Jic and activate transcription. J. Biol. Chem. 272, 11336–11343.PubMedCrossRefGoogle Scholar
  67. 67.
    Girard, L., Hanna, Z., Beaulieu, N., Hoemann, C. D., Simard, C., Kozak, C. A., and Jolicoeur, P. (1996) Frequent provirus insertional mutagenesis of Notchl in thymomas of MMTVD/myc transgenic mice suggests a collaboration of c-myc and Notchl for oncogenesis. Genes Dey. 10, 1930–1944.CrossRefGoogle Scholar
  68. 68.
    Pear, W. S., Aster, J. C., Scott, M. L., Hasserjian, R. P., Soffer, B., Sklar, J., and Baltimore, D. (1996) Exclusive development of T cell neoplasms in mice transplanted with bone marrow expressing activated Notch alleles. J. Exp. Med. 183, 2283–2291.PubMedCrossRefGoogle Scholar
  69. 69.
    Washburn, T., Schweighoffer, E., Gridley, T., Chang, D., Fowlkes, B. J., Cado, D., and Robey, E. (1997) Notch activity influences the aß versus yS T cell lineage decision. Cell 88, 833–843.Google Scholar
  70. 70.
    Linette, G. P., Grusby, M. J., Hedrick, S. M., Hansen, T. H., Glimcher, L. H., and Korsmeyer, S. J. (1994)and1–2 is upregulated at the CD4+CD8+ stage during positive selection and promotes thymocyte differentiation at several control points. Immunity 1, 197–205.Google Scholar
  71. 71.
    Lucas, B., Vasseur, F., and Penit, C. (1994) Production, selection, and maturation ofthymocytes with high surface density of TCR. J. Immunol. 153, 53–62.PubMedGoogle Scholar
  72. 72.
    Rooke, R., Waltzinger, C., Benoist, C., and Mathis, D. (1997) Targeted complementation of MHC class II deficiency by intrathymic delivery of recombinant adenoviruses. Immunity 7, 123–134.PubMedCrossRefGoogle Scholar
  73. 73.
    Huesmann, M., Scott, B., Kisielow, P., and von Boehmer, H. (1991) Kinetics and efficiency of positive selection in the thymus of normal and T cell receptor transgenic mice. Cell 66, 533–540.PubMedCrossRefGoogle Scholar
  74. 74.
    Ernst, B., Surh, C. D., and Sprent, J. (1995) Thymic selection and cell division. J. Exp. Med. 182, 961–971.PubMedCrossRefGoogle Scholar
  75. 75.
    Nakayama, K.-I., Nakayama, K., Negishi, I., Kuida, K., Shinkai, Y., Louie, M., Fields, I. E., Lucas, P. J., Stewart, V., Alt, F. W., and Loh, D. Y. (1993) Disappearance of the lymphoid system in Bc1–2 homozygous mutant chimeric mice. Science 261, 1584–1588.PubMedCrossRefGoogle Scholar
  76. 76.
    Abbas, A. K., Murphy, K. M., and Sher, A. (1996) Functional diversity of helper T lymphocytes. Nature 383, 787–793.PubMedCrossRefGoogle Scholar
  77. 76a.
    Takeda, S., Rodewald, H. R., Arakawa, H., Bluethmann, H., and Shimizu, T (1996) MHC class II molecules are not required for survival of newly generated CD4+ T cells, but affect their longterm life span. Immunity 5, 217–228.PubMedCrossRefGoogle Scholar
  78. 77.
    Kozieradzki, I., Kundig, T., Kishihara, K., Ong, C. J., Chiu, D., Wallace, V. A., Kawai, V. A., Timms, E., J. Ionescu, J., Ohashi, P., Marth, J. D., Mak, T. W., and Penninger, J. M. (1997) T cell development in mice expressing splice variants of the protein tyrosine phosphatase CD45. J. Immunol. 158, 3130–3139.PubMedGoogle Scholar
  79. 78.
    Hostert, A., Tolaini, M., Festenstein, R., McNeill, L., Malissen, B., Williams, O., Zamoyska, R., and Kioussis, D. (1997) A CD8 genomic fragment that directs subset-specific expression of CD8 in transgenic mice. J. Immunol. 158, 4270–4281.PubMedGoogle Scholar
  80. 79.
    Siu, G., Wurster, A. L., Duncan, D. D., Soliman, T. M., and Hedrick, S. M. (1994) A transcriptional silencer controls the developmental expression of the CD4 gene. EMBO J. 13, 3570–3579.PubMedGoogle Scholar
  81. 80.
    Salmon, P., Giovane, A., Wasylyk, B., and Klatzmann, D. (1993) Characterization of the human CD4 gene promoter: transcription from the CD4 gene core promoter is tissue-specific and is activated by Ets proteins. Proc. Natl. Acad. Sci. USA 90, 7739–7743.PubMedCrossRefGoogle Scholar
  82. 81.
    Siu, G., Wurster, A. L., Lipsick, J. S., and Hedrick, S. M. (1992) Expression of the CD4 gene requires a Myb transcription factor. Mol. Cell. Biol. 12, 1592–1604.PubMedGoogle Scholar
  83. 82.
    Duncan, D. D., Stupakoff, A., Hedrick, S. M., Marcu, K. B., and Siu, G. (1995) A Mycassociated zinc finger protein binding site is one of four important functional regions in the CD4 promoter. Mol. Cell. Biol. 15, 3179–3186.PubMedGoogle Scholar
  84. 83.
    Badiani, P., Corbella, P., Kioussis, D., Marvel, J., and Weston, K. (1994) Dominant interfering alleles define a role for c-Myb in T-cell development. Genes Dey. 8, 770–782.CrossRefGoogle Scholar
  85. 84.
    Badiani, P. A., Kioussis, D., Swirsky, D. M., Lampert, I. A., and Weston, K. (1996) T-cell lymphomas in v-Myb transgenic mice. Oncogene 13, 2205–2212.PubMedGoogle Scholar
  86. 85.
    Sawada, S. and Littman, D. R. (1991) Identification and characterization of a T-cell-specific enhancer adjacent to the murine CD4 gene. Mol. Cell. Biol. 11, 5506–5515.PubMedGoogle Scholar
  87. 86.
    Blum, M. D., Wong, G. T., Higgins, K. M., Sunshine, M. J., and Lacy, E. (1993) Reconstitution of the subclass-specific expression of CD4 in thymocytes and peripheral T cells of transgenic mice: identification of a human CD4 enhancer. J. Exp. Med. 177, 1343–1358.PubMedCrossRefGoogle Scholar
  88. 87.
    Sawada, S., Scarborough, J. D., Killeen, N., and Littman, D. R. (1994) A lineage-specific transcriptional silencer regulates CD4 gene expression during T lymphocyte development. Cell 77, 917–929.PubMedCrossRefGoogle Scholar
  89. 88.
    Sawada, S. and Littman, D. R. (1993) A heterodimer of HEB and an E 12-related protein interacts with the CD4 enhancer and regulates its activity in T-cell lines. Mol. Cell. Biol. 13, 5620–5628.Google Scholar
  90. 89.
    Wurster, A. L., Siu, G., Leiden, J. M., and Hedrick, S. M. (1994) Elf-1 binds to a critical element in a second CD4 enhancer [published erratum appears in Mol Cell Biol 1994 Dec; 14(12),8493]. Mol. Cell. Biol. 14, 6452–6463.PubMedGoogle Scholar
  91. 90.
    Gillespie, F. P., Doros, L., Vitale, J., Blackwell, C., Gosselin, J., Snyder, B. W., and Wadsworth, S. C. (1993) Tissue-specific expression of human CD4 in transgenic mice. Mol. Cell. Biol. 13, 2952–2958.PubMedGoogle Scholar
  92. 91.
    Hanna, Z., Simard, C., Laperriere, A., and Jolicoeur, P. (1994) Specific expression of the human CD4 gene in mature CD4+ CD8- and immature CD4+ CD8+ T cells and in macrophages of transgenic mice. Mol. Cell. Biol. 14, 1084–1094.PubMedGoogle Scholar
  93. 92.
    Killeen, N., Sawada, S., and Littman, D. R. (1993) Regulated expression of human CD4 rescues helper T cell development in mice lacking expression of endogenous CD4. EMBO J. 12, 1547–1553.PubMedGoogle Scholar
  94. 93.
    Salmon, P., Boyer, O., Lores, P., Jami, J., and Klatzmann, D. (1996) Characterization of an intronless CD4 minigene expressed in mature CD4 and CD8 T cells, but not expressed in immature thymocytes. J. Immunol. 156, 1873–1879.PubMedGoogle Scholar
  95. 94.
    Duncan, D. D., Adlam, M., and Siu, G. (1996) Asymmetric redundancy in CD4 silencer function. Immunity 4, 301–311.PubMedCrossRefGoogle Scholar
  96. 95.
    Adlam, M., Duncan, D. D., Ng, D. K., and Siu, G. (1997) Positive selection induces CD4 promoter and enhancer function. Int. Immunol. 9, 877–887.PubMedCrossRefGoogle Scholar
  97. 96.
    Uematsu, Y., Donda, A., and De Libero, G. (1997) Thymocytes control the CD4 gene differently from mature T lymphocytes. Int. Immunol. 9, 179–187.PubMedCrossRefGoogle Scholar
  98. 97.
    Kydd, R., Lundberg, K., Vremec, D., Harris, A. W., and Shortman, K. (1995) Intermediate steps in thymic positive selection. Generation of CD4–8+ T cells in culture from CD4+8+ CD4’t’t8+, and CD4+8’t’t thymocytes with up-regulated levels of TCR-CD3. J. Immunol. 155, 3806–3814.PubMedGoogle Scholar
  99. 98.
    Donda, A., Schulz, M., Burki, K., De Libero, G., and Uematsu, Y. (1996) Identification and characterization of a human CD4 silencer. Eur. J. Immunol. 26, 493–500.PubMedCrossRefGoogle Scholar
  100. 99.
    Sasai, Y., Kageyama, R., Tagawa, Y., Shigemoto, R., and Nakanishi, S. (1992) Two mammalian helix-loop-helix factors structurally related to Drosophila hairy and Enhancer of split. Genes Del). 6, 2620–2634.CrossRefGoogle Scholar
  101. 100.
    Poussier, P. and Julius, M. (1994) Thymus independent T cell development and selection in the intestinal epithelium. Ann. Rev. Immunol. 12, 521–553.CrossRefGoogle Scholar
  102. 101.
    Gao, M. H. and Kavathas, P. B. (1993) Functional importance of the cyclic AMP response element-like decamer motif in the CD8 alpha promoter. J. Immunol. 150, 4376–4385.PubMedGoogle Scholar
  103. 102.
    Hambor, J. E., Mennone, J., Coon, M. E., Hanke, J. H., and Kavathas, P. (1993) Identification and characterization of an Alu-containing, T-cell-specific enhancer located in the last intron of the human CD8 alpha gene. Mol. Cell. Biol. 13, 7056–7070.PubMedGoogle Scholar
  104. 103.
    Hanke, J. H., Hambor, J. E., and Kavathas, P. (1995) Repetitive Alu elements form a cruciform structure that regulates the function of the human CD8 alpha T cell-specific enhancer. J. Mol. Biol. 246, 63–73.PubMedCrossRefGoogle Scholar
  105. 104.
    Kieffer, L. J., Bennett, J. A., Cunningham, A. C., Gladue, R. P., McNeish, J., Kavathas, P. B., and Hanke, J. H. (1996) Human CD8 alpha expression in NK cells but not cytotoxic T cells of transgenic mice. Int. Immunol. 8, 1617–1626.PubMedCrossRefGoogle Scholar
  106. 105.
    Hostert, A., Tolaini, M., Roderick, K., Harker, N., Norton, T., and Kioussis, D. (1997) A region in the CD8 gene locus that directs expression to the mature CD8 T cell subset in transgenic mice. Immunity 7, 525–536.PubMedCrossRefGoogle Scholar
  107. 106.
    Ellmeier, W., Sunshine, M. J., Losos, K., Hatam, F., and Littman, D. R. (1997) An enhancer that directs lineage-specific expression of CD8 in positively selected thymocytes and mature T cells. Immunity 7, 537–547.PubMedCrossRefGoogle Scholar
  108. 107.
    Gao, M. H., Walz, M., and Kavathas, P. B. (1996) Post-transcriptional regulation associated with control of human CD8a expression of CD4+ T cells. Immunogenetics 45, 130–135.PubMedCrossRefGoogle Scholar
  109. 108.
    Guidos, C. J., Williams, C. J., Wu, G. E., Paige, C. J., and Danska, J. S. (1995) Development of CD4+CD8+ thymocytes in RAG-deficient mice through a T cell receptor ß chain-independent pathway. J. Exp. Med. 181, 1187–1195.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1998

Authors and Affiliations

  • Cynthia J. Guidos

There are no affiliations available

Personalised recommendations