Genetic Regulation of Apoptosis in the Mouse Thymus

  • Barbara A. Osborne
  • Sallie W. Smith
  • Kelly A. McLaughlin
  • Lisa Grimm
  • Grant Morgan
  • Richard A. Goldsby
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 406)


Recently, it has become clear that apoptosis, a form of programmed cell death, plays an active role in the maintenance of homeostasis of cells as well in the morphological sculpting of organisms during development1,2. Some of the best characterized examples of apoptosis may be found in the immune system. For example, apoptosis is the mechanism used during negative selection in the thymus to remove self-reactive T cells3–5. Thymic T cells also are quite susceptible to induction of apoptosis by either glucocorticoids or ionizing radiation6,7. Additionally, more recent data indicate that peripheral lymphocytes undergo apoptosis following a variety of different stimuli and, in many instances, cell death in activated peripheral T cells may be traced to Fas/FasL interactions8–10.


Glucocorticoid Receptor Negative Selection Reactive Oxygen Intermediate Thymocyte Apoptosis Cell Death Gene 
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.
    Ellis, R., J. Yuan, and H. R. Horvitz, Mechanisms and functions of cell death. Annu. Rev. Cell Biol. 7: 663 (1991).PubMedCrossRefGoogle Scholar
  2. 2.
    Schwartz, L. M. and B. A. Osborne, Programmed cell death, apoptosis and killer genes. Immunol. Today 14: 582 (1993).PubMedCrossRefGoogle Scholar
  3. 3.
    Swat, W., L. Ignatowicz, H. von Boehmer, and P. Kisielow, Clonal deletion of immature CD4+ CD8+ thymocytes in suspension culture by extrathymic antigen-presenting cells. Nature 351: 150 (1991).PubMedCrossRefGoogle Scholar
  4. 4.
    Smith, C. A., G. Williams, R. Kingston, E. J. Jenkinson, and J. T. Owen, Antibodies to CD3/T-cell receptor complex induces death by apoptosis in immature T cells in thymic culture. Nature 337: 181 (1989).PubMedCrossRefGoogle Scholar
  5. 5.
    Murphy, K. M., A. B. Heimberger, and D. Y. Loh, Induction by antigen of intrathymic apoptosis of CD4+ CD8+ TCRIO thymocytes in vivo. Science 250: 1720 (1990).Google Scholar
  6. 6.
    Wyllie, A. H., Glucocorticoid induced thymocyte apoptosis is associated with endogenous endonuclease activation. Nature 284: 555 (1980).PubMedCrossRefGoogle Scholar
  7. 7.
    Sellins, K. and J.J. Cohen, Gene induction by y-irradiation leads to DNA fragmentation in lymphocytes. J. lmmunol. 139: 3199 (1987).Google Scholar
  8. 8.
    Dhein, J., H. Walczak, C. Baumler, K-M. Debatin, and P. H. Krammer, Autocrine T-cell suicide mediated by APO-1/(Fas/CD95). Nature 373: 438 (1995).PubMedCrossRefGoogle Scholar
  9. 9.
    Brunner, T., R. J. Mogil, D. LaFace, N.J. Yoo, A. Mahoubi, F. Echeverri, S.J. Martin, W.R. Force, D. H. Lynch, C.F. Ware and D.R. Green, Cell-autonomous Fas (CD95)/Fas-ligand interaction mediates activation-induced apoptosis in T-cell hybridomas. Nature 373: 441 (1995).PubMedCrossRefGoogle Scholar
  10. 10.
    Ju, S-T, D. J. Panka, H. Cul, R. Ettinger, M. El-Khatib, D. H. Sherr, B. Z. Stanger, and A. Marshak-Rothstein, Fas (CD95)/FasL interactions required for programmed cell death after T-cell activation. Nature 373: 444 (1995).PubMedCrossRefGoogle Scholar
  11. 11.
    Vacchio, M., V. Papadopoulus, and J. D. Ashwell, Steroid production in the thymus: implications for thymocyte selection. J. Exp. Med. 179: 1835 (1994).PubMedCrossRefGoogle Scholar
  12. 12.
    King, L.B., M.S. Vacchio, R. Hunziker, D. H. Margulies, and J. D. Ashwell, A targeted glucocorticoid receptor antisense transgene increases thymocyte apoptosis and alters thymocyte development. Immunity 5: 647 (1995).CrossRefGoogle Scholar
  13. 13.
    White, J., A. Herman, A. M. Pullen, R. Kubo, J. Kappler, and P. Marrack, The VP-specific superantigen staphylococcal enterotoxin B: Stimulation of mature T cells and clonal deletion in neonatal mice. Cell 56: 27 (1989).PubMedCrossRefGoogle Scholar
  14. 14.
    Kisielow, P., H. Bluthmann, U. D. 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
  15. 15.
    Sha, W., C. Nelson, R. Newberry, D. Kranz, J. 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
  16. 16.
    Berg, L., G. Frank and M.M. Davis, The effects of MHC gene dosage and allelic variation on T cell receptor selection. Cell 60: 1043 (1990).PubMedCrossRefGoogle Scholar
  17. 17.
    MacDonald, H. R. and R. K. Lees, Programmed death of autoreactive thymocytes. Nature 343: 624 (1990).CrossRefGoogle Scholar
  18. 18.
    Winslow, G. M., M. T. Scherer, J. W. Kappler, and P. Marrack, Detection and biochemical characterization of the mouse mammary tumor virus 7 superantigen (Mls-la). Cell 71: 719 (1992).PubMedCrossRefGoogle Scholar
  19. 19.
    Schwartz, L. M., The role of cell death genes during development. BioEssays 13: 389 (1991).PubMedCrossRefGoogle Scholar
  20. 20.
    Cohen, J. J. and R. Duke, Glucocorticoid activation of a calcium-dependent endonuclease in thymocyte nuclei leads to cell death. J. Immunol. 132: 38 (1984).PubMedGoogle Scholar
  21. 21.
    Shi, Y., M. Szaly, L. Paskar, M. Boyer, B. Singh, and D. R. Green, Activation-induced cell death in T cell hybridomas is due to apoptosis. J. Immunol. 144: 3326 (1990).PubMedGoogle Scholar
  22. 23.
    Lau, L. and D. Nathans, Expression of a set of growth-related immediate early genes in BALB/c 3T3 cells: Coordinate regulation with c-fos or c-myc. Proc. Natl. Acad. Sci. (USA) 84: 1182 (1987).CrossRefGoogle Scholar
  23. 24.
    Watson, M. A. and J. Milbrandt, The NGFI-B gene, a transcriptionally inducible member of the steroid receptor gene superfamily: genomic structure and expression in rat brain after seizure induction. Mol. Cell. Biol. 9: 4213 (1989).PubMedGoogle Scholar
  24. 25.
    Liu, Z.-G., S. W. Smith, K. A. McLauglin, L. M. Schwartz, and B. A. Osborne, Apoptotic signals through the T-cell receptor of a T-cell hybrid require the immediate-early gene nur77. Nature 36: 281 (1994).CrossRefGoogle Scholar
  25. 26.
    Woronicz, J. D., B. Calnan, V. Ngo, and A. Winoto, Requirement for the orphan steroid receptor Nur77 in apoptosis of T-cell hybridomas. Nature 367: 277 (1994).PubMedCrossRefGoogle Scholar
  26. 27.
    Calnan, B.J., S. Szychowski, F. K-M. Chan, D. Cado, and A. Winoto, Arole for the orphan steroid receptor Nur77 in apoptosis accompanying antigen-induced negative selection. Immunity 3: 273 (1995).PubMedCrossRefGoogle Scholar
  27. 28.
    Ramakrishnan, N. and G. Catravas, N-(2-mercaptoethyl)-1,3-propanediamine (WR-1065) protects thymocytes from programmed cell death. J. Immunol. 148: 1817 (1992).PubMedGoogle Scholar
  28. 29.
    Mayer, M. and M. Nobel, N-acetyl-L-cysteine is a pluripotent protector against cell death and enhancer of trophic factor-mediated cell survival in vitro. Proc. Natl. Acad. Sci. USA 91: 7496 (1994).PubMedCrossRefGoogle Scholar
  29. 30.
    Iwata, M., M. Mukai, Y. Nakai, and R. Iseki, Retinoic acid inhibits activation-induced apoptosis inT cell-hybridoms and thymocytes. J. Immunol. 149: 3302 (1992).PubMedGoogle Scholar
  30. 31.
    Sandstrom, P. A., M. Mannie, and T. M. Buttke, Inhibition of activation-induced death in T cell hybridomas by thiol antioxidative stress as a mediator of apoptosis. J. Leukoc. Biol. 55: 221 (1994).PubMedGoogle Scholar
  31. 32.
    Hockenbery, D., Z. Oltvai, X. Yin, C. Milliman, and S. Korsmeyer, Bc1–2 functions in an antioxidant pathway to prevent apoptosis. Cell 75: 241 (1993).PubMedCrossRefGoogle Scholar
  32. 33.
    Lowe, S, E. M. Schmitt, S. W. Smith, B. A. Osborne, and T. Jacks, p53 is required for radiation-induced apoptosis in mouse thymocytes. Nature 362: 847 (1993).PubMedCrossRefGoogle Scholar
  33. 34.
    Clarke, A.R., C.A. Purdie, D.J. Harrison, R.G. Morris, C.C. Bird, M.L. Hooper, and A. Wyllie, Thymocyte apoptosis induced by p53- dependent pathways. Nature 362: 849 (1993).PubMedCrossRefGoogle Scholar
  34. 35.
    Yonish-Rouach, E., D. Resnitzky, J. Lotem, L. Sachs, A. Kimchi, and M. Oren, Wild-type p53 induces apoptosis of myeloid leukemic cells that is inhibited by interleukin-6. Nature 352: 345 (1991).PubMedCrossRefGoogle Scholar
  35. 36.
    Jacks, T., L. Remington, B. O. Williams, E. Schmidt, S. Halacimi, R. T. Bronson, and R. A. Weinberg, Tumor spectrum analysis in p53 mutant mice. Curr. Biol. 4:1 (1994).Google Scholar
  36. 37.
    Dieken, E. S. and R. L.Miesfeld, Transcriptional transactivation functions localized to the glucocorticoid receptor N terminus are necessary for steroid induction of lymphocyte apoptosis. Mol. Cell. Biol. 92: 589 (1992).Google Scholar
  37. 38.
    Owens, G. P., W. Hahn, and J. J. Cohen, Identification of mRNAs associated with programmed cell death in immature thymocytes. Mol. Cell. Biol. 11: 4177 (1991).Google Scholar
  38. 39.
    Waga, S., G. J. Hannon, D. Beach, and B. Stillman, The p21 inhibitor of cyclin-dependent kinases controls DNA replication by interaction with PCNA. Nature 369: 520 (1994).CrossRefGoogle Scholar
  39. 40.
    Caelles, C., A. Helmberg, and M. Karin, p53-dependent apoptosis in the absence of transcriptional activation of p53 target genes. Nature 370: 220 (1994).PubMedCrossRefGoogle Scholar
  40. 41.
    Shi, Y., J. M. Glynn, L. J. Guilbert, T. G. Cotter, R. Bissonette, and D. R. Green, Role for c-myc in activation-induced apoptotic death in T cell hybridomas. Science 257: 212 (1992).PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1996

Authors and Affiliations

  • Barbara A. Osborne
    • 1
    • 2
  • Sallie W. Smith
    • 1
  • Kelly A. McLaughlin
    • 2
  • Lisa Grimm
    • 2
  • Grant Morgan
    • 1
  • Richard A. Goldsby
    • 3
  1. 1.Department of Veterinary and Animal SciencesUniversity of MassachusettsAmherstUSA
  2. 2.Program in Molecular & Cellular BiologyUniversity of MassachusettsAmherstUSA
  3. 3.Department of BiologyAmherst CollegeAmherstUSA

Personalised recommendations