Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

BH3-only Bcl-2 family member Bim is required for apoptosis of autoreactive thymocytes

A Corrigendum to this article was published on 04 July 2002

Abstract

During lymphocyte development, the assembly of genes coding for antigen receptors occurs by the combinatorial linking of gene segments. The stochastic nature of this process gives rise to lymphocytes that can recognize self-antigens, thereby having the potential to induce autoimmune disease. Such autoreactive lymphocytes can be silenced by developmental arrest or unresponsiveness (anergy)1, or can be deleted from the repertoire by cell death1. In the thymus, developing T lymphocytes (thymocytes) bearing a T-cell receptor (TCR)–CD3 complex that engages self-antigens are induced to undergo programmed cell death (apoptosis)2,3,4, but the mechanisms ensuring this ‘negative selection’ are unclear. We now report that thymocytes lacking the pro-apoptotic Bcl-2 family member Bim5,6 (also known as Bcl2l11) are refractory to apoptosis induced by TCR–CD3 stimulation. Moreover, in transgenic mice expressing autoreactive TCRs that provoke widespread deletion, Bim deficiency severely impaired thymocyte killing. TCR ligation upregulated Bim expression and promoted interaction of Bim with Bcl-XL, inhibiting its survival function. These findings identify Bim as an essential initiator of apoptosis in thymocyte-negative selection.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Bim is required for TCR ligation-induced thymocyte killing.
Figure 2: Bim is required for Staphylococcus enterotoxin B (SEB)-induced deletion of TCRVβ8+ thymocytes in fetal thymic organ culture.
Figure 3: Bim is required for the deletion of OT-II TCR transgenic thymocytes induced by superantigen as well as by peptide injection.
Figure 4: Bim is required for deletion of autoreactive HY male antigen-specific thymocytes in anti-HY TCR transgenic mice.
Figure 5: TCR–CD3 ligation increases expression of Bim and promotes binding of Bim to Bcl-XL.

Similar content being viewed by others

References

  1. Nossal, G. J. V. Negative selection of lymphocytes. Cell 76, 229–239 (1994).

    Article  CAS  Google Scholar 

  2. Swat, W., Ignatowicz, L., von Boehmer, H. & Kisielow, P. Clonal deletion of immature CD4+ CD8+ thymocytes in suspension culture by extrathymic antigen-presenting cells. Nature 351, 150–153 (1991).

    Article  ADS  CAS  Google Scholar 

  3. Surh, C. D. & Sprent, J. T-cell apoptosis detected in situ during positive and negative selection in the thymus. Nature 372, 100–103 (1994).

    Article  ADS  CAS  Google Scholar 

  4. Clayton, L. K. et al. T-cell receptor ligation by peptide/MHC induces activation of a caspase in immature thymocytes: the molecular basis of negative selection. EMBO J. 16, 2282–2293 (1997).

    Article  CAS  Google Scholar 

  5. O'Connor, L. et al. Bim: a novel member of the Bcl-2 family that promotes apoptosis. EMBO J. 17, 384–395 (1998).

    Article  CAS  Google Scholar 

  6. Bouillet, P. et al. Proapoptotic Bcl-2 relative Bim required for certain apoptotic responses, leukocyte homeostasis, and to preclude autoimmunity. Science 286, 1735–1738 (1999).

    Article  CAS  Google Scholar 

  7. Gross, A., McDonnell, J. M. & Korsmeyer, S. J. Bcl-2 family members and the mitochondria in apoptosis. Genes Dev. 13, 1899–1911 (1999).

    Article  CAS  Google Scholar 

  8. Strasser, A., O'Connor, L. & Dixit, V. M. Apoptosis signaling. Annu. Rev. Biochem. 69, 217–245 (2000).

    Article  CAS  Google Scholar 

  9. Smith, K. G. C., Strasser, A. & Vaux, D. L. CrmA expression in T lymphocytes of transgenic mice inhibits CD95 (Fas/APO-1)-transduced apoptosis, but does not cause lymphadenopathy or autoimmune disease. EMBO J. 15, 5167–5176 (1996).

    Article  CAS  Google Scholar 

  10. Newton, K., Harris, A. W., Bath, M. L., Smith, K. G. C. & Strasser, A. A dominant interfering mutant of FADD/Mort1 enhances deletion of autoreactive thymocytes and inhibits proliferation of mature T lymphocytes. EMBO J. 17, 706–718 (1998).

    Article  CAS  Google Scholar 

  11. Walsh, C. M. et al. A role for FADD in T cell activation and development. Immunity 8, 439–449 (1998).

    Article  CAS  Google Scholar 

  12. Sentman, C. L., Shutter, J. R., Hockenbery, D., Kanagawa, O. & Korsmeyer, S. J. bcl-2 inhibits multiple forms of apoptosis but not negative selection in thymocytes. Cell 67, 879–888 (1991).

    Article  CAS  Google Scholar 

  13. Strasser, A., Harris, A. W. & Cory, S. Bcl-2 transgene inhibits T cell death and perturbs thymic self-censorship. Cell 67, 889–899 (1991).

    Article  CAS  Google Scholar 

  14. Huang, D. C. S. & Strasser, A. BH3-only proteins—essential initiators of apoptotic cell death. Cell 103, 839–842 (2000).

    Article  CAS  Google Scholar 

  15. Zong, W. X., Lindsten, T., Ross, A. J., MacGregor, G. R. & Thompson, C. B. BH3-only proteins that bind pro-survival Bcl-2 family members fail to induce apoptosis in the absence of Bax and Bak. Genes Dev. 15, 1481–1486 (2001).

    Article  CAS  Google Scholar 

  16. Nakayama, T. et al. In vivo calcium elevations in thymocytes with T cell receptors that are specific for self ligands. Science 257, 96–99 (1992).

    Article  ADS  CAS  Google Scholar 

  17. Martin, S. & Bevan, M. J. Antigen-specific and nonspecific deletion of immature cortical thymocytes caused by antigen injection. Eur. J. Immunol. 27, 2726–2736 (1997).

    Article  CAS  Google Scholar 

  18. Jenkinson, E. J., Kingston, R. & Owen, J. J. Newly generated thymocytes are not refractory to deletion when the α/β component of the T cell receptor is engaged by the superantigen staphylococcal enterotoxin B. Eur. J. Immunol. 20, 2517–2520 (1990).

    Article  CAS  Google Scholar 

  19. Barnden, M. J., Allison, J., Heath, W. R. & Carbone, F. R. Defective TCR expression in transgenic mice constructed using cDNA-based α- and β-chain genes under the control of heterologous regulatory elements. Immunol. Cell Biol. 76, 34–40 (1998).

    Article  CAS  Google Scholar 

  20. Bouillet, P., Cory, S., Zhang, L.-C., Strasser, A. & Adams, J. M. Degenerative disorders caused by Bcl-2 deficiency are prevented by loss of its BH3-only antagonist Bim. Dev. Cell 1, 645–653 (2001).

    Article  CAS  Google Scholar 

  21. von Boehmer, H. Developmental biology of T cells in T cell-receptor transgenic mice. Annu. Rev. Immunol. 8, 531–556 (1990).

    Article  CAS  Google Scholar 

  22. Strasser, A., Harris, A. W., Von Boehmer, H. & Cory, S. Positive and negative selection of T cells in T cell receptor transgenic mice expressing a bcl-2 transgene. Proc. Natl Acad. Sci. USA 91, 1376–1380 (1994).

    Article  ADS  CAS  Google Scholar 

  23. Puthalakath, H., Huang, D. C. S., O'Reilly, L. A., King, S. M. & Strasser, A. The pro-apoptotic activity of the Bcl-2 family member Bim is regulated by interaction with the dynein motor complex. Mol. Cell 3, 287–296 (1999).

    Article  CAS  Google Scholar 

  24. Ma, A. et al. Bclx regulates the survival of double-positive thymocytes. Proc. Natl Acad. Sci. USA 92, 4763–4767 (1995).

    Article  ADS  CAS  Google Scholar 

  25. Ogilvy, S. et al. Constitutive bcl-2 expression throughout the hematopoietic compartment affects multiple lineages and enhances progenitor cell survival. Proc. Natl Acad. Sci. USA 96, 14943–14948 (1999).

    Article  ADS  CAS  Google Scholar 

  26. Grillot, D. A. M., Merino, R. & Nuñez, G. Bcl-xL displays restricted distribution during T cell development and inhibits multiple forms of apoptosis but not clonal deletion in transgenic mice. J. Exp. Med. 182, 1973–1983 (1995).

    Article  CAS  Google Scholar 

  27. Calnan, B. J., Szychowski, S., Chan, F. K., Cado, D. & Winoto, A. A role for the orphan steroid receptor Nur77 in apoptosis accompanying antigen-induced negative selection. Immunity 3, 273–282 (1995).

    Article  CAS  Google Scholar 

  28. Zhou, T. et al. Inhibition of Nur77/Nurr1 leads to inefficient clonal deletion of self-reactive T cells. J. Exp. Med. 183, 1879–1892 (1996).

    Article  CAS  Google Scholar 

  29. Suzuki, A. et al. T cell-specific loss of Pten leads to defects in central and peripheral tolerance. Immunity 14, 523–534 (2001).

    Article  CAS  Google Scholar 

  30. Dijkers, P. F., Medemadagger, R. H., Lammers, J. J., Koenderman, L. & Coffer, P. J. Expression of the pro-apoptotic Bcl-2 family member Bim is regulated by the forkhead transcription factor FKHR-L1. Curr. Biol. 10, 1201–1204 (2000).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We are grateful to H. von Boehmer and W. Heath for HY-TCR and OT-II TCR transgenic mice. We thank A. Naughton and C. Tilbrook for animal care, A. Harris, J. Miller, D. Huang and L. O'Reilly for discussions and critical comments on the manuscript, and G. Smyth and R. Thomson for statistical advice. This work was supported by fellowships and grants from the National Health and Medical Research Council (Canberra), the Dr Josef Steiner Cancer Research Foundation (Bern), the Leukemia and Lymphoma Society of America, the Anti-Cancer Council of Victoria and the NIH.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Andreas Strasser.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bouillet, P., Purton, J., Godfrey, D. et al. BH3-only Bcl-2 family member Bim is required for apoptosis of autoreactive thymocytes. Nature 415, 922–926 (2002). https://doi.org/10.1038/415922a

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/415922a

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing