Gene Regulation in T-Cell Lineage Commitment

  • Ellen V. Rothenberg
Part of the Contemporary Immunology book series (CONTIM)


This chapter considers the molecular mechanisms that operate during the commitment of a pluripotent hematopoietic cell to differentiate within the T-cell lineage. This commitment event, or sequence of events, results in the establishment of a novel stable pattern of transcriptional regulation that can be inherited by the daughters of committed cells, which will define them as T-cells wherever they migrate in the body. Therefore, the essential changes in the cells during commitment are changes in gene regulation.


Gene Expression Program Lineage Commitment Thymocyte Development Thymocyte Differentiation Thymocyte Subset 
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.


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  1. 1.
    Malissen, M., Gillet, A., Ardouin, L., Bouvier, G., Trucy, J., Ferrier, P., Vivier, E., and Malissen, B. (1995) Altered T cell development in mice with a targeted mutation of the CD3-E gene. EMBO J. 14, 4641–4653.PubMedGoogle Scholar
  2. 2.
    Wilson, A. and MacDonald, H. R. (1995) Expression of genes encoding the pre-TCR and CD3 complex during thymus development. Int. Immunol. 7, 1659–1664.PubMedGoogle Scholar
  3. 3.
    Georgopoulos, K., Bigby, M., Wang, J.-H., Molnar, A., Wu, P., Winandy, S., and Sharpe, A. (1994) The Ikaros gene is required for the development of all lymphoid lineages. Cell 79, 143–156.PubMedGoogle Scholar
  4. 4.
    Georgopoulos, K., Morgan, B. A., and Moore, D. D. (1992) Functionally distinct isoforms of the CRE-BP DNA-binding protein mediate activity of a T-cell-specific enhancer. Mol. Cell. Biol. 12, 747–757.PubMedGoogle Scholar
  5. 5.
    Hallberg, B., Thornell, A., Holm, M., and Grundstrom, T. (1992) SEF 1 binding is important for T cell specific enhancers of genes for T cell receptor-CD3 subunits. Nucleic Acids Res. 20, 6495–6499.PubMedGoogle Scholar
  6. 6.
    Ogawa, E., Maruyama, M., Kagoshima, H., Inuzuka, M., Lu, J., Satake, M., Shigesada, K., and Ito, Y. (1993) PEBP2/PEA2 represents a family of transcription factors homologous to the products of the Drosophila runt gene and the human AML1 gene. Proc. Natl. Acad. Sci. USA 90, 6859–6863.PubMedGoogle Scholar
  7. 7.
    Brandle, D., Muller, S., Muller, C., Hengartner, H., and Pircher, H. (1994) Regulation of RAG-1 and CD69 expression in the thymus during positive and negative selection. Eur. J. Immunol. 24, 145–151.PubMedGoogle Scholar
  8. 8.
    Brown, S. T., Miranda, G. A., Galic, Z., Hartman, I. Z., Lyon, C. J., and Aguilera, R. J. (1997) Regulation of the RAG-1 promoter by the NF-Y transcription factor. J. Immunol. 158, 5071–5074.PubMedGoogle Scholar
  9. 9.
    Ernst, P., Hahm, K., Trinh, L., Davis, J. N., Roussel, M. F., Turck, C. W., and Smale, S. T. (1996) A potential role for Elf-1 in terminal transferase gene regulation. Mol. Cell. Biol. 16, 6121–6131.PubMedGoogle Scholar
  10. 10.
    Schatz, D. G., Oettinger, M. A., and Schlissel, M. S. (1992) V(D)J recombination, molecular biology and regulation. Annu. Rev. Immunol. 10, 359–383.PubMedGoogle Scholar
  11. 11.
    Willerford, D. M., Swat, W., and Alt, F. W. (1996) Developmental regulation of V(D)J recombination and lymphocyte differentiation. Curr. Opin. Gen. Devel. 6, 603–609.Google Scholar
  12. 12.
    Biassoni, R., Verdiani, S., Cambiaggi, A., Romeo, P.-H., Ferrini, S., and Moretta, L. (1993) Human CD3-CD 16+ natural killer cells express the hGATA-3 T cell transcription factor and an unrearranged 2.3-kb TcR S transcript. Eur. J. Immunol. 23, 1083–1087.PubMedGoogle Scholar
  13. 13.
    Furley, A. J., Chan, L. C., Mizutani, S., Ford, A. M., Weilbaecher, K., Pegram, S. M., and Greaves, M. F. (1987) Lineage specificity of rearrangement and expression of genes encoding the T cell receptor-T3 complex and immunoglobulin heavy chain in leukemia. Leukemia 1, 644–652.PubMedGoogle Scholar
  14. 14.
    Greenberg, J. M., Quertermous, T., Seidman, J. G., and Kersey, J. H. (1986) Human T cell y-chain gene rearrangements in acute lymphoid and nonlymphoid leukemia: comparison with the T cell receptor I3-chain gene. J. Immunol. 137, 2043–2049.PubMedGoogle Scholar
  15. 15.
    Siden, E. J. (1993) Regulated expression of germline antigen receptor genes in mast cell lines from the murine embryo. J. Immunol. 150, 4427–4437.PubMedGoogle Scholar
  16. 16.
    Soloff, R. S. K., Wang, T.-G., Lybarger, L., Dempsey, D., and Chervenak, R. (1995) Transcription of the TCR-ß locus initiates in adult murine bone marrow. J. Immunol. 154, 3888–3901.PubMedGoogle Scholar
  17. 17.
    Giese, K., Kingsley, C., Kirshner, J. R., and Grosschedl, R. (1995) Assembly and function of a TCRa enhancer complex is dependent on LEF-1-induced DNA bending and multiple protein-protein interactions. Genes Dev. 9, 995–1008.PubMedGoogle Scholar
  18. 18.
    Henderson, A. J., McDougall, S., Leiden, J., and Calame, K. L. (1994) GATA elements are necessary for the activity and tissue specificity of the T-cell receptor I3-chain transcriptional enhancer. Mol. Cell. Biol. 14, 4286–4294.PubMedGoogle Scholar
  19. 19.
    Hernandez-Munain, C. and Krangel, M. S. (1994) Regulation of the T-cell receptor S enhancer by functional cooperation between c-Myb and core-binding factors. Mol. Cell. Biol. 14, 473–483.PubMedGoogle Scholar
  20. 20.
    Hsiang, Y. H., Spencer, D., Wang, S., Speck, N. A., and Raulet, D. H. (1993) The role of viral enhancer “core” motif-related sequences in regulating T cell receptor-y and -S gene expression. J. Immunol. 150, 3905–3916.PubMedGoogle Scholar
  21. 21.
    Leiden, J. M. (1993) TranscriptionalregulationofTcellreceptorgenes.Ann. Rev. Immunol.11,539–570. Google Scholar
  22. 22.
    Hsiang, Y. H., Goldman, J. P., and Raulet, D. H. (1995) The role of c-Myb or a related factor in regulating the T cell receptor y gene enhancer. J. Immunol. 154, 5195–5204.PubMedGoogle Scholar
  23. 23.
    Wotton, D., Ghysdael, J., Wang, S., Speck, N. A., and Owen, M. J. (1994) Cooperative binding of Ets-1 and core binding factor to DNA. Mol. Cell. Biol. 14, 840–850.PubMedGoogle Scholar
  24. 24.
    Bruno, L., Rocha, B., Rolink, A., von Boehmer, H., and Rodewald, H.-R. (1995) Intra-and extra-thymic expression of the pre-T cell receptor a gene. Eur. J. Immunol. 25, 1877–1882.PubMedGoogle Scholar
  25. 25.
    Saint-Ruf, C., Ungewiss, K., Groettrup, L. B., Fehling, H. J., and von Boehmer, H. (1994) Analysis and expression of a cloned pre-T cell receptor gene. Science 266, 1208–1212.PubMedGoogle Scholar
  26. 26.
    Nagishi, I., Motoyama, N., Nakayama, K.-I., Nakayama, K., Senju, S., Hatakeyama, S., Zhang, Q., Chan, A. C., and Loh, D. Y. (1995) Essential role for ZAP-70 in both positive and negative selection of thymocytes. Nature 376, 435–438.Google Scholar
  27. 27.
    Wallace, V. A., Kawai, K., Levelt, C. N., Kishihara, K., Molina, T., Timms, E., Pircher, H., Penninger, J., Ohashi, P. S., Eichmann, K., and Mak, T. W. (1995) T lymphocyte development in p561ck deficient mice: allelic exclusion of the TcR f3 locus is incomplete but thymocyte development is not restored by TcR f3 or TcR aß transgenes. Eur. J. Immunol. 25, 1312–1318.PubMedGoogle Scholar
  28. 28.
    Biondi, A., Paganin, C., Rossi, V., Benvestito, S., Perlmutter, R. M., Mantovani, A., and Allavena, P. (1991) Expression of lineage-restricted protein tyrosine kinase genes in human natural killer cells. Eur. J. Immunol. 21, 843–846.PubMedGoogle Scholar
  29. 29.
    Chan, A. C., Iwashima, M., Turck, C. W., and Weiss, A. (1992) ZAP-70, a 70 kd protein-tyrosine kinase that associates with the TCR chain. Cell 71, 649–662.PubMedGoogle Scholar
  30. 30.
    Perlmutter, R. M., Marth, J. D., Lewis, D. B., Peet, R., Ziegler, S. F., and Wilson, C. B. (1988) Structure and expression of lck transcripts in human lymphoid cells. J. Cell. Biochem. 38, 117–126.PubMedGoogle Scholar
  31. 31.
    Anderson, S. J., Levin, S. D., and Perlmutter, R. M. (1993) Protein tyrosine kinase p56“ controls allelic exclusion of T-cell receptor 13-chain genes. Nature 365, 552–554.PubMedGoogle Scholar
  32. 32.
    Hattori, N., Kawamoto, H., and Katsura, Y. (1996) Isolation of the most immature population of murine fetal thymocytes that includes progenitors capable of generating T, B, and myeloid cells. J. Exp. Med. 184, 1901–1908.PubMedGoogle Scholar
  33. 33.
    Allen, J. M., Forbush, K. A., and Perlmutter, R. M. (1992) Functional dissection of the lck proximal promoter. Mol. Cell. Biol. 12, 2758–2768.PubMedGoogle Scholar
  34. 33a.
    McCracken, S., Leung, S., Bosselut, R., Ghysdael, J., and Miyamoto, N. G. (1994) Myb and Ets transcription factors are required for activity of the human lck type I promoter. Oncogene 9, 3609–3615.PubMedGoogle Scholar
  35. 34.
    Jain, J., Loh, C., and Rao, A. (1995) Transcriptional regulation of the IL2 gene. Curr. Opin. Immunol. 7, 333–342.PubMedGoogle Scholar
  36. 35.
    Rothenberg, E. V. and Ward, S. B. (1996) A dynamic assembly of diverse transcription factors integrates activation and cell-type information for interleukin-2 gene regulation. Proc. Natl. Acad. Sci. USA 93, 9358–9365.PubMedGoogle Scholar
  37. 36.
    Serfling, E., Avots, A., and Neumann, M. (1995) The architecture of the interleukin-2 promoter: a reflection of T lymphocyte activation. Biochem. Biophys. Acta 1263, 181–200.PubMedGoogle Scholar
  38. 37.
    Avots, A., Hoffmeyer, A., Flory, E., Cimanis, A., Rapp, U. R., and Serfling, E. (1997) GABP factors bind to a distal interleukin 2 (IL-2) enhancer and contribute to c-Raf-mediated increase in IL-2 induction. Mol. Cell. Biol. 17, 4381–4389.PubMedGoogle Scholar
  39. 38.
    Brown, M. A. and Hural, J. (1997) Functions of IL-4 and control of its expression. Crit. Rev. Immunol. 17, 1–32.PubMedGoogle Scholar
  40. 39.
    Chuvpilo, S., Schomberg, C., Gerwig, R., Heinfling, A., Reeves, R., Grummt, F., and Serfling, E. (1993) Multiple closely-linked NFAT/octamer and HMG I(Y) binding sites are part of the interleukin-4 promoter. Nucl. Acids Res. 21, 5694–5704.PubMedGoogle Scholar
  41. 40.
    Rooney, J. W., Hoey, T., and Glimcher, L. H. (1995) Coordinate and cooperative roles for NF-AT and AP-1 in the regulation of the murine IL-4 gene. Immunity 2, 473–483.PubMedGoogle Scholar
  42. 41.
    Szabo, S. J., Gold, J. S., Murphy, T. L., and Murphy, K. M. (1993) Identification of cis-acting regulatory elements controlling interleukin-4 gene expression in T cells: roles for NF-Y and NF-ATc. Mol. Cell. Biol. 13, 4793–4805.PubMedGoogle Scholar
  43. 42.
    Ho, I.-C., Hodge, M. R., Rooney, J. W., and Glimcher, L. H. (1996) The proto-oncogene c-maf is responsible for tissue-specific expression of interleukin-4 Cell 85, 973–983.PubMedGoogle Scholar
  44. 43.
    Li-Weber, M., Krafft, H., and Krammer, P. H. (1993) A novel enhancer element in the human IL-4 promoter is suppressed by a position-independent silencer. J. Immunol. 151, 1371–1382.PubMedGoogle Scholar
  45. 44.
    Li-Weber, M., Salgame, P., Hu, C., Davydov, I. V., and Krammer, P. H. (1997) Differential interaction of nuclear factors with the PRE-I enhancer element of the human IL-4 promoter in different T cell subsets. J. Immunol. 158, 1194–1200.PubMedGoogle Scholar
  46. 45.
    Zheng, W.-P. and Flavell, R. A. (1997) The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4 cells. Cell 89, 587–596.PubMedGoogle Scholar
  47. 46.
    Horta, M. D., Fu, K. C., Koizumi, H., Young, J. D., and Liu, C. C. (1996) Cell-free conversion of a ubiquitous nuclear protein into a killer-cell-specific form that binds to the NF-P enhancer element in the mouse perforin gene. Eur. J. Biochem. 238, 639–646.PubMedGoogle Scholar
  48. 47.
    Lichtenheld, M. G. and Podack, E. R. (1992) Structure and function of the murine perforin promoter and upstream region. Reciprocal gene activation or silencing in perforin positive and negative cells. J. Immunol. 149, 2619–2626.PubMedGoogle Scholar
  49. 48.
    Lichtenheld, M. G., Podack, E. R., and Levy, R. B. (1995) Transgenic control of perforin gene expression. J. Immunol. 154, 2153–2163.PubMedGoogle Scholar
  50. 49.
    Youn, B. S., Kim, K. K., and Kwon, B. S. (1996) A critical role of Sp1- and Ets-related transcription factors in maintaining CTL-specific expression of the mouse perforin gene. J. Immunol. 157, 3499–3509.PubMedGoogle Scholar
  51. 50.
    Zhang, Y. and Lichtenheld, M. G. (1997) Non-killer cell-specific transcription factors silence the perforin promoter. J. Immunol. 158, 1734–1741.PubMedGoogle Scholar
  52. 51.
    Lynch, D. H., Ramsdell, F., and Alderson, M. R. (1995) Fas and FasL in the homeostatic regulation of immune responses. Immunol. Today 16, 569–574.PubMedGoogle Scholar
  53. 52.
    Waterhouse, P., Penninger, J. M., Timms, E., Wakeham, A., Shahinian, A., Lee, K. P., Thompson, C. B., Griesser, H., and Mak, T. W. (1995) Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science 270, 985–988.Google Scholar
  54. 53.
    Morrison, S. J., Prowse, K. R., Ho, P., and Weissman, I. L. (1996) Telomerase activity in hematopoietic cells is associated with self-renewal potential. Immunity 5, 207–216.PubMedGoogle Scholar
  55. 54.
    Weng, N. P., Levine, B. L., June, C. H., and Hodes, R. J. (1996) Regulated expression oftelomerase activity in human T lymphocyte development and activation. J. Exp. Med. 183, 2471–2479.PubMedGoogle Scholar
  56. 55.
    Carè, A., Testa, U., Bassani, A., Tritarelli, E., Montesoro, E., Samoggia, P., Cianetti, L., and Peschle, C. (1994) Coordinate expression and proliferative role of HOXB genes in activated adult T lymphocytes. Mol. Cell. Biol. 14, 4872–4877.PubMedGoogle Scholar
  57. 56.
    Helgason, C. D., Sauvageau, G., Lawrence, H. J., Largman, C., and Humphries, R. K. (1996) Overexpression of HOXB4 enhances the hematopoietic potential of embryonic stem cells differentiated in vitro. Blood 87, 2740–2749.PubMedGoogle Scholar
  58. 57.
    Sauvageau, G., Thorsteinsdottir, U., Eaves, C. J., Lawrence, H. J., Largman, C., Lansdorp, P. M., and Humphries, R. K. (1995) Overexpression of HOXB4 in hematopoietic cells causes the selective expansion of more primitive populations in vitro and in vivo. Genes Dey. 9, 1753–1765.Google Scholar
  59. 58.
    Candéias, S., Muegge, K., and Dumm, S. K. (1997) IL-7 receptor and VDJ recombination: trophic versus mechanistic actions. Immunity 6, 501–508.PubMedGoogle Scholar
  60. 59.
    Rodewald, H.-R., Ogawa, M., Haller, C., Waskow, C., and DiSanto, J. P. (1997) Pro-thymocyte expansion by c-kit and the common cytokine receptor y chain is essential for repertoire formation. Immunity 6, 265–272.PubMedGoogle Scholar
  61. 60.
    Kingston, R., Jenkinson, E. J., and Owen, J. J. T. (1985) A single stem cell can recolonize an embryonic thymus, producing phenotypically distinct T-cell populations. Nature 317, 811–813.PubMedGoogle Scholar
  62. 61.
    Godfrey, D. I. and Zlotnik, A. (1993) Control points in early T-cell development. Immunol. Today 14, 547–553.PubMedGoogle Scholar
  63. 62.
    Shortman, K. and Wu, L. (1996) Early T lymphocyte progenitors. Annu. Rev. Immunol. 14, 29–47.PubMedGoogle Scholar
  64. 63.
    Diamond, R. A., Ward, S. B., Owada-Makabe, K., Wang, H., and Rothenberg, E. V. (1997) Different developmental arrest points in RAG2-/’ and scid thymocytes on two genetic backgrounds: developmental choices and cell death mechanisms before TCR gene rearrangement. J. Immunol. 158, 4052–4064.PubMedGoogle Scholar
  65. 64.
    Wang, H., Diamond, R. A., and Rothenberg, E. V. (1997) Cross-lineage expression of Ig-ß (B29) in thymocytes: positive and negative gene regulation to establish T-cell identity, submitted.Google Scholar
  66. 65.
    Moore, T. A. and Zlotnik, A. (1995) T-lineage commitment and cytokine responses of thymic progenitors. Blood 86, 1850–1860.PubMedGoogle Scholar
  67. 66.
    Zúniga-Pflücker, J. C. and Lenardo, M. J. (1996) Regulation of thymocyte development from immature progenitors. Curr. Opin. Immunol. 8, 215–224.PubMedGoogle Scholar
  68. 67.
    Godfrey, D. I., Kennedy, J., Mombaerts, P., Tonegawa, S., and Zlotnik, A (1994) Onset of TCR-ß gene rearrangement and role of TCR-ß expression during CD3–CD4-CD8- thymocyte differentiation. J. Immunol. 152, 4783–4792.PubMedGoogle Scholar
  69. 68.
    Ismaili, J., Antica, M., and Wu, L. (1996) CD4 and CD8 expression and T cell antigen receptor gene rearrangement in early thymic precursor cells. Eur. J. Immunol. 26, 731–737.PubMedGoogle Scholar
  70. 69.
    Petrie, H. T., Livak, F., Burtrum, D., and Mazel, S. (1995) T cell receptor gene recombination patterns and mechanisms: cell death, rescue, and T cell production. J. Exp. Med. 182, 121–127.PubMedGoogle Scholar
  71. 70.
    Candéias, S., Hardy, R. R., Li, Y. S., and Staerz, U. D. (1994) T cell receptor V138.2 gene germ-line transcription: an early event of lymphocyte differentiation. Eur. J. Immunol. 24, 3073–3081.PubMedGoogle Scholar
  72. 71.
    Rothenberg, E. V., Chen, D., and Diamond, R. A. (1993) Functional and phenotypic analysis of thymocytes in SCID mice: evidence for functional response transitions before and after the SCID arrest point. J. Immunol. 151, 3530–3546.PubMedGoogle Scholar
  73. 72.
    Davidson, E. H. (1990). How embryos work: a comparative view of diverse modes of cell fate specification. Development 108, 365–389.PubMedGoogle Scholar
  74. 73.
    Spangrude, G. J. and Scollay, R. (1990) Differentiation of hematopoietic stem cells in irradiated mouse thymic lobes: kinetics and phenotype of progeny. J. Immunol. 145, 3661–3668.PubMedGoogle Scholar
  75. 74.
    Ardavin, C., Wu, L., Li, C. L., and Shortman, K. (1993) Thymic dendritic cells and T cells develop simultaneously in the thymus from a common precursor population. Nature 362, 761–763.PubMedGoogle Scholar
  76. 75.
    Matsuzaki, Y., Gyotoku, J.-I., Ogawa, M., Nishikawa, S.-I., Katsura, Y., Gachelin, G., and Nakauchi, H. (1993) Characterization of c-kit positive intrathymic stem cells that are restricted to lymphoid differentiation. J. Exp. Med. 178, 1283–1292.PubMedGoogle Scholar
  77. 76.
    Rodewald, H.-R., Moingeon, P., Lucich, J. L., Dosiou, C., Lopez, P., and Reinherz, E. L. (1992) A population of early fetal thymocytes expressing FcgammaRII/III contains precursors of T lymphocytes and natural killer cells. Cell 69, 139–150.PubMedGoogle Scholar
  78. 77.
    Wu, L., Antica, M., Johnson, G. R., Scollay, R., and Shortman, K. (1991) Developmental potential of the earliest precursor cells from the adult mouse thymus. J. Exp. Med. 174, 1617–1627.PubMedGoogle Scholar
  79. 78.
    Wu, L., Li, C.-L., and Shortman, K. (1996) Thymic dendritic cell precursors: relationship to the T lymphocyte lineage and phenotype of the dendritic cell progeny. J. Exp. Med. 184, 903–911.PubMedGoogle Scholar
  80. 79.
    Zúniga-Pflücker, J. C., Jiang, D., and Lenardo, M. J. (1995) Requirement for TNF-a and IL-la in fetal thymocyte commitment and differentiation. Science 268, 1906–1909.PubMedGoogle Scholar
  81. 80.
    Kawamoto, H., Ohmura, K., and Katsura, Y. (1997) Direct evidence for the commitment of hematopoietic stem cells to T, B, and myeloid lineages in murine fetal liver. Int. Immunol. 9, 1011–1019.PubMedGoogle Scholar
  82. 81.
    Rodewald, H. R., Kretzschmar, K., Takeda, S., Hohl, C., and Dessing, M. (1994) Identification of pro-thymocytes in murine fetal blood: T lineage commitment can precede thymus colonization. EMBO J. 13, 4229–4240.PubMedGoogle Scholar
  83. 82.
    Spits, H., Lanier, L. L., and Phillips, J. H. (1995) Development of human T and natural killer cells. Blood 85, 2654–2670.PubMedGoogle Scholar
  84. 83.
    Morrison, S. J., Shah, N. M., and Anderson, D. J. (1997) Regulatory mechanisms in stem cell biology. Cell 88, 287–298.PubMedGoogle Scholar
  85. 84.
    Res, P., Martinez-Caceres, E., Jaleco, A. C., Staal, F., Noteboom, E., Weijer, K., and Spits, H. (1996) CD34+ CD38d’m cells in the human thymus can differentiate into T, natural killer, and dendritic cells but are distinct from pluripotent stem cells. Blood 87, 5196–5206.Google Scholar
  86. 85.
    Sanchez, M. J., Muench, M. O., Roncarolo, M. G., Lanier, L. L., and Phillips, J. H. (1994) Identification of a common T/natural killer cell progenitor in human fetal thymus. J Exp. Med. 180, 569–576.Google Scholar
  87. 86.
    Wang, J.-H., Nichogiannopoulou, A., Wu, L., Sun, L., Sharpe, A. H., Bigby, M., and Georgopoulos, K. (1996) Selective defects in the development of the fetal and adult lymphoid system in mice with an Ikaros null mutation. Immunity 5, 537–549.Google Scholar
  88. 87.
    Borrello, M. A. and Phipps, R. P. (1996) The B/macrophage cell: an elusive link between CD5+ B lymphocytes and macrophages. Immunol. Today 17, 471–475.PubMedGoogle Scholar
  89. 88.
    Cumano, A., Paige, C. J., Iscove, N. N., and Brady, G. (1992) Bipotential precursors of B cells and macrophages in murine fetal liver. Nature 356, 612–615.PubMedGoogle Scholar
  90. 89.
    Cross, M. A., Heyworth, C. M., Murrell, A. M., Bockamp, E. O., Dexter, T. M., and Green, A. R. (1994) Expression of lineage restricted transcription factors precedes lineage specific differentiation in a multipotent haemopoietic progenitor cell line. Oncogene 9, 3013–3016.PubMedGoogle Scholar
  91. 90.
    Hu, M., Krause, D., Greaves, M., Sharkis, S., Dexter, M., Heyworth, C., and Enver, T. (1997) Multilineage gene expression precedes commitment in the hemopoietic system. Genes Dev. 11, 774–785.PubMedGoogle Scholar
  92. 91.
    Sposi, N. M., Zon, L. I., Carè, A., Valtieri, M., Testa, U., Gabbianelli, M., Mariani, G., BotteroGoogle Scholar
  93. L., Mather, C., Orkin, S. H., and Peschle, C. (1992) Cell cycle-dependent initiation and lineage-dependent abrogation of GATA-1 expression in pure differentiating hematopoietic progenitors. Proc. Natl. Acad. Sci. USA 89, 6353–6357.PubMedGoogle Scholar
  94. 92.
    Blom, B., Res, P., Noteboom, E., Weijer, K., and Spits, H. (1997) Prethymic CD34+ progenitors capable of developing into T cells are not committed to the T cell lineage. J. Immunol. 158, 3571–3577.PubMedGoogle Scholar
  95. 93.
    McCubrey, J. A., Steelman, L. S., Risser, R. G., and McKearn, J. P. (1989) Structure and expression of the T cell receptor gamma locus in pre-B and early hemopoietic cells. Eur. J. Immunol. 19, 2303–2308.PubMedGoogle Scholar
  96. 94.
    Okada, A., Mendelsohn, M., and Alt, F. (1994) Differential activation of transcription versus recombination of transgenic T cell receptor 13 variable region gene segments in B and T lineage cells. J. Exp. Med. 180, 261–272.PubMedGoogle Scholar
  97. 95.
    Bassuk, A. G. and Leiden, J. M. (1997) The role of Ets transcription factors in the development and function of the mammalian immune system. Adv. Immunol. 64, 65–104.PubMedGoogle Scholar
  98. 96.
    Bockamp, E.-O., McLaughlin, F., Murrell, A., and Green, A. R. (1994) Transcription factors and the regulation of haemopoiesis: lessons from GATA and SCL proteins. BioEssays 16, 481–488.PubMedGoogle Scholar
  99. 97.
    Shivdasani, R. A. and Orkin, S. H. (1996) The transcriptional control of hematopoiesis. Blood 87, 4025–4039.PubMedGoogle Scholar
  100. 98.
    Clevers, H. C. and Grosschedl, R. (1996) Transcriptional control of lymphoid development, lessons from gene targeting. Immunol. Today 17, 336–343.PubMedGoogle Scholar
  101. 99.
    Clevers, H. C., Oosterwegel, M. A., and Georgopoulos, K. (1993) Transcription factors in early T-cell development. Immunol. Today 14, 591–596.PubMedGoogle Scholar
  102. 100.
    Fitzsimmons, D. and Hagman, J. (1996) Regulation of gene expression at early stages of B-cell and T-cell differentiation. Curr. Opin. Immunol. 8, 166–174.PubMedGoogle Scholar
  103. 101.
    Singh, H. (1996) Gene targeting reveals a hierarchy of transcription factors regulating specification of lymphoid cell fates. Curr. Opin. Immunol. 8, 160–165.PubMedGoogle Scholar
  104. 102.
    Okuda, T., van Deursen, J., Hiebert, S. W., Grosveld, G., and Downing, J. R. (1996) AML1, the target of multiple chromosomal translocations in human leukemia, is essential for normal fetal liver hematopoiesis. Cell 84, 321–330.PubMedGoogle Scholar
  105. 103.
    Wang, Q., Stacy, T., Binder, M., Marin-Padilla, M., Sharpe, A. H., and Speck, N. A. (1996) Disruption of the Cbfa2 gene causes necrosis and hemorrhaging in the central nervous system and blocks definitive hematopoiesis. Proc. Natl. Acad. Sci. USA 93, 3444–3449.PubMedGoogle Scholar
  106. 104.
    Pandolfi, P. P., Roth, M. E., Karis, A., Leonard, M. W., Dzierzak, E., Grosveld, F. G., Engel, J. D., and Lindenbaum, M. H. (1995) Targeted disruption of the GATA3 gene causes severe abnormalities in the nervous system and in fetal liver haematopoiesis. Nature Genetics 11, 40–44.Google Scholar
  107. 105.
    Schilham, M. W., Oosterwegel, M. A., Moerer, P., Ya, J., de Boer, P. A. J., Van de Wetering, M., Verbeek, S., Lamers, W. H., Kruisbeek, A. M., Cumano, A., and Clevers, H. (1996) Defects in cardiac outflow tract formation and pro-B-lymphocyte expansion in mice lacking Sox-4. Nature 380, 711–714.PubMedGoogle Scholar
  108. 106.
    Verbeek, S., Izon, D., Hofhuis, F., Robanus-Maandag, E., to Riele, H., Van de Wetering, M., Oosterwegel, M., Wilson, A., MacDonald, H. R., and Clevers, H. (1995) An HMG-box-containing T-cell factor required for thymocyte differentiation. Nature 374, 70–74.Google Scholar
  109. 107.
    Baker, S. J. and Reddy, E. P. (1995) B cell differentiation: role of E2A and Pax5/BSAP transcription factors. Oncogene 11, 413–426.PubMedGoogle Scholar
  110. 108.
    Opstelten, D. (1996) B lymphocyte development and transcription regulation in vivo. Adv. Immunol. 63, 197–268.PubMedGoogle Scholar
  111. 109.
    Bain, G., Robanus Maandag, E. C., Izon, D. J., Amsen, D., Kruisbeek, A. M., Weintraub, B. C., Krop, I., Schissel, M. S., Feeney, A. J., van Roon, M., van der Valk, M., to Riele, H. P. J., Berns, A., and Murre, C. (1994) E2A proteins are required for proper B cell development and initiation of immunoglobulin gene rearrangements. Cell 79, 885–892.PubMedGoogle Scholar
  112. 110.
    Lin, H. and Grosschedl, R. (1995) Failure of B-cell differentiation in mice lacking the transcription factor EBF. Nature 376, 263–267.PubMedGoogle Scholar
  113. 111.
    Nutt, S. L., Urbanek, P., Rolink, A., and Busslinger, M. (1997) Essential functions of PaxS (BSAP) in pro-B cell development: difference between fetal and adult B lymphopoiesis and reduced V-to-DJ recombination at the IgH locus. Genes Dev. 11, 476–491.Google Scholar
  114. 112.
    Urbanek, P. Wang, Z. Q., Fetka, I., Wagner, E. F., and Busslinger, M. (1994) Complete block of early B cell differentiation and altered patterning of the posterior midbrain in mice lacking PaxS/B SAP. Cell 79 901–912.Google Scholar
  115. 113.
    Zhuang, Y., Soriano, P., and Weintraub, H. (1994) The helix-loop-helix gene E2A is required for B cell formation. Cell 79, 875–884.PubMedGoogle Scholar
  116. 114.
    Zhuang, Y., Cheng, P., and Weintraub, H. (1996) B-lymphocyte development is regulated by the combined dosage of three basic helix-loop-helix genes, E2A, E2–2, and HEB. Mol. Cell. Biol. 16, 2898–2905.Google Scholar
  117. 115.
    Morgan, B., Sun, L., Avitahl, N., Andrikopoulos, K., Ikeda, T., Gonzales, E., Wu, P., Neben, S., and Georgopoulos, K. (1997) Aiolos, a lymphoid restricted transcription factor that interacts with Ikaros to regulate lymphocyte differentiation. EMBO J. 16, 2004–2013.Google Scholar
  118. 116.
    Bain, B., Engel, I., Robanus Maandag, E. C., to Riele, H. P., Voland, J. R., Sharp, L. L., Chun, J., Huey, B., Pinkel, D., and Murre, C. (1997) E2A deficiency leads to abnormalities in T-cell development and to rapid development of T-cell lymphomas. Mol. Cell. Biol. 17, 4782–4791.PubMedGoogle Scholar
  119. 117.
    Schilham, M. W., Moerer, P., Cumano, A., and Clevers, H. C. (1997) Sox-4 facilitates thymocyte differentiation. Eur. J. Immunol. 27, 1292–1295.PubMedGoogle Scholar
  120. 118.
    Hattori, N., Kawamoto, H., Fujimoto, S., Kuno, K., and Katsura, Y. (1996) Involvement of transcription factors TCF-1 and GATA-3 in the initiation of the earliest step of T cell development in the thymus. J. Exp. Med. 184, 1137–1147.PubMedGoogle Scholar
  121. 119.
    Ting, C.-N., Olson, M. C., Barton, K. P., and Leiden, J. M. (1996) Transcription factor GATA-3 is required for development of the T-cell lineage. Nature 384, 474–478.PubMedGoogle Scholar
  122. 120.
    Zúniga-Pflücker, J. C., Schwartz, H. L., and Lenardo, M. J. (1993) Gene transcription in differentiating immature T cell receptorDeg thymocytes resembles antigen-activated mature T cells. J. Exp. Med. 178, 1139–1149.PubMedGoogle Scholar
  123. 121.
    Mombaerts, P., Clarke, A. R., Rudnicki, M. A., Iacomini, J., Itohara, S., Lafaille, J. J., Wang, L., Ichikawa, Y., Jaenisch, R., Hooper, M. L., and Tonegawa, S. (1992) Mutations in T-cell antigen receptor genes a and ß block thymocyte development at different stages. Nature 360, 225–231.Google Scholar
  124. 122.
    Dubart, A., Romeo, P. H., Vainchenker, W., and Dumenil, D. (1996) Constitutive expression of GATA-1 interferes with the cell-cycle regulation. Blood 87, 3711–3721.PubMedGoogle Scholar
  125. 123.
    Weiss, M. J. and Orkin, S. H. (1995) Transcription factor GATA-1 permits survival and maturation of erythroid precursors by preventing apoptosis. Proc. Natl. Acad. Sci. USA 92, 9623–9627.PubMedGoogle Scholar
  126. 124.
    Barton, K., Muthusamy, N., Chanyangam, M., Fischer, C., Clendenin, C., and Leiden, J. M. (1996) Defective thymocyte proliferation and IL-2 production in transgenic mice expressing a dominant-negative form of CREB. Nature 379, 81–85.PubMedGoogle Scholar
  127. 125.
    Clausell, A. and Tucker, P. W. (1994) Functional analysis of the Vy3 promoter of the murine y6 T-cell receptor. Mol. Cell. Biol. 14, 803–814.PubMedGoogle Scholar
  128. 126.
    Clevers, H. C., Dunlap, S., Wileman, T. E., and Terhorst, C. (1988) Human CD3-c gene contains three miniexons and is transcribed from a non-TATA promoter. Proc. Natl. Acad. Sci. USA 85, 8156–8160.PubMedGoogle Scholar
  129. 127.
    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 CD8a gene. Mol. Cell. Biol. 13, 7056–7070.PubMedGoogle Scholar
  130. 128.
    Hernandez-Munain, C., Lauzurica, P., and Krangel, M. S. (1996) Regulation of T cell receptor S gene rearrangement by c-Myb. J. Exp. Med. 183, 289–293.PubMedGoogle Scholar
  131. 129.
    Hummler, C., Cole, T. J., Blendy, J. A., Ganss, R., Aguzzi, A., Schmid, W., Beermann, F., and Schutz, G. (1994) Targeted mutation of the CREB gene: compensation within the CREB/ATF family of transcription factors. Proc. Natl. Acad. Sci. USA 91, 5647–5651.PubMedGoogle Scholar
  132. 130.
    Lauzurica, P., Zhong, X.-P., Krangel, M. S., and Roberts, J. L. (1997) Regulation of T cell receptor S gene rearrangement by CBF/PEBP2. J. Exp. Med. 185, 1193–1201.PubMedGoogle Scholar
  133. 131.
    Oosterwegel, M., Van de Wetering, M., and Clevers, H. (1993) HMG box proteins in early T-cell differentiation. Thymus 22, 67–81.PubMedGoogle Scholar
  134. 132.
    Punturieri, A., Shirakata, Y., Bovolenta, C., Kikuchi, G., and Coligan, J. E. (1993) Multiple cis-acting elements are required for proper transcription of the mouse V81 T cell receptor promoter. J. Immunol. 150, 139–150.PubMedGoogle Scholar
  135. 133.
    Salomoni, P., Perrotti, D., Martinez, R., Franceschi, C., and Calabretta, B. (1997) Resistance to apoptosis in CTLL-2 cells constitutively expressing c-Myb is associated with induction of BCL-2 expression and Myb-dependent regulation of bel-2 promoter activity. Proc. Natl. Acad. Sci. USA 94, 3296–3301.PubMedGoogle Scholar
  136. 134.
    Wotton, D., Lake, R. A., Farr, C. J., and Owen, M. J. (1995) The high mobility group transcription factor, SOX4, transactivates the human CD2 enhancer. J. Biol. Chem. 270, 7515–7522.PubMedGoogle Scholar
  137. 135.
    Yamada, T., Hitomi, Y., Satake, M., and Oikawa, T. (1995) Differential expression of the T cell receptor/CD3 genes and their lymphoid-specific transcription factor genes in murine T cell x fibroblast and T cell x B cell hybrids. Eur. J. Immunol. 25, 2710–2713.PubMedGoogle Scholar
  138. 136.
    Yang, L., Lanier, E. R., and Kraig, E. (1997) Identification of a novel, spliced variant of CREB that is preferentially expressed in the thymus. J. Immunol. 158, 2522–2525.PubMedGoogle Scholar
  139. 137.
    Carlyle, J. R., Michie, A. M., Furlonger, C., Nakano, T., Lenardo, M. J., Paige, C. J., and ZúnigaPflücker, J. C. (1997) Identification of a novel developmental stage marking lineage commitment of progenitor thymocytes. J. Exp. Med. 186, 173–182.PubMedGoogle Scholar
  140. 138.
    Leclercq, G., Debacker, V., De Smedt, M., and Plum, J. (1996) Differential effects of interleukin15 and interleukin-2 on differentiation of bipotential T/natural killer progenitor cells. J. Exp. Med. 184, 325–336.PubMedGoogle Scholar
  141. 139.
    Rothenberg, E. V., Diamond, R. A., Pepper, K. A., and Yang, J. A. (1990) Interleukin-2 gene inducibility in T cells prior to T-cell receptor expression: changes in signaling pathways and gene expression requirements during intrathymic maturation. J. Immunol. 144, 1614–1624.PubMedGoogle Scholar

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© Springer Science+Business Media New York 1998

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  • Ellen V. Rothenberg

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