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.

  • Article
  • Published:

Defective thymocyte apoptosis and accelerated autoimmune diseases in TRAIL−/− mice

This article has been updated

Abstract

TRAIL, the tumor necrosis factor-related apoptosis-inducing ligand, selectively induces apoptosis of tumor cells, but not most normal cells. Its role in normal, nontransformed tissues is not clear. We report here that mice deficient in TRAIL have a severe defect in thymocyte apoptosis—thus, thymic deletion induced by T cell receptor ligation is severely impaired. TRAIL-deficient mice are also hypersensitive to collagen-induced arthritis and streptozotocin-induced diabetes and develop heightened autoimmune responses. Thus, TRAIL mediates thymocyte apoptosis and is important in the induction of autoimmune diseases.

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: TRAIL−/− mice and susceptibility to autoimmune diseases.
Figure 2: Anti-collagen immune responses.
Figure 3: Thymocyte apoptosis in vivo and in vitro.
Figure 4: Effects of TRAIL blockade on thymocyte apoptosis.
Figure 5: Roles of TRAIL in fetal thymus organ culture.
Figure 6: Ovalbumin-induced thymocyte apoptosis in vivo.
Figure 7: Mtv-9–induced T cell deletion in vivo.

Similar content being viewed by others

Change history

  • 18 February 2003

    spelling was corrected for online and print versions

References

  1. Singer, G.G. & Abbas, A.K. The Fas antigen is involved in peripheral but not thymic deletion of T lymphocytes in T cell receptor transgenic mice. Immunity 1, 365–371 (1994).

    Article  CAS  Google Scholar 

  2. Kishimoto, H., Surh, C.D. & Sprent, J. A role for Fas in negative selection of thymocytes in vivo. J. Exp. Med. 187, 1427–1438 (1998).

    Article  CAS  Google Scholar 

  3. Wiley, S.R. et al. Identification and characterization of a new member of the TNF family that induces apoptosis. Immunity 3, 673–682 (1995).

    Article  CAS  Google Scholar 

  4. Pan, G. et al. An antagonist decoy receptor and a death domain-containing receptor for TRAIL. Science 277, 815–818 (1997).

    Article  CAS  Google Scholar 

  5. Pan, G., Ni, J., Yu, G., Wei, Y.F. & Dixit, V.M. TRUNDD, a new member of the TRAIL receptor family that antagonizes TRAIL signalling. FEBS Lett. 424, 41–45 (1998).

    Article  CAS  Google Scholar 

  6. Schneider, P. et al. Characterization of two receptors for TRAIL. FEBS Lett. 416, 329–334 (1997).

    Article  CAS  Google Scholar 

  7. Sheikh, M.S. et al. p53-dependent and -independent regulation of the death receptor KILLER/DR5 gene expression in response to genotoxic stress and tumor necrosis factor α. Cancer Res. 58, 1593–1598 (1998).

    CAS  PubMed  Google Scholar 

  8. Sheridan, J.P. et al. Control of TRAIL-induced apoptosis by a family of signaling and decoy receptors. Science 277, 818–821 (1997).

    Article  CAS  Google Scholar 

  9. Walczak, H. et al. TRAIL-R2: a novel apoptosis-mediating receptor for TRAIL. EMBO J. 16, 5386–5397 (1997).

    Article  CAS  Google Scholar 

  10. Screaton, G.R. et al. TRICK2, a new alternatively spliced receptor that transduces the cytotoxic signal from TRAIL. Curr. Biol. 7, 693–696 (1997).

    Article  CAS  Google Scholar 

  11. Sprick, M.R. et al. FADD/MORT1 and caspase-8 are recruited to TRAIL receptors 1 and 2 and are essential for apoptosis mediated by TRAIL receptor 2. Immunity 12, 599–609 (2000).

    Article  CAS  Google Scholar 

  12. Bodmer, J.L. et al. TRAIL receptor-2 signals apoptosis through FADD and caspase-8. Nat. Cell Biol. 2, 241–243 (2000).

    Article  CAS  Google Scholar 

  13. Zhang, X.D., Zhang, X.Y., Gray, C.P., Nguyen, T. & Hersey, P. Tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis of human melanoma is regulated by smac/DIABLO release from mitochondria. Cancer Res. 61, 7339–7348 (2001).

    CAS  PubMed  Google Scholar 

  14. Deng, Y., Lin, Y. & Wu, X. TRAIL-induced apoptosis requires Bax-dependent mitochondrial release of Smac/DIABLO. Genes Dev. 16, 33–45 (2002).

    Article  CAS  Google Scholar 

  15. Abulencia, J.P., Gaspard, R., Quackenbush, J. & Konstantopoulos, K. Discovery and characterization of differentially regulated genes in the chondrocytic cell line T/C-28a2 under dynamic fluid shear. FASEB J. 16, A656–657 (2002).

    Google Scholar 

  16. Schneider, P. et al. TRAIL receptors 1 (DR4) and 2 (DR5) signal FADD-dependent apoptosis and activate NF-κB. Immunity 7, 831–836 (1997).

    Article  CAS  Google Scholar 

  17. Wu, G.S., Burns, T.F., Zhan, Y., Alnemri, E.S. & El-Deiry, W.S. Molecular cloning and functional analysis of the mouse homologue of the KILLER/DR5 tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) death receptor. Cancer Res. 59, 2770–2775 (1999).

    CAS  PubMed  Google Scholar 

  18. Jeremias, I., Herr, I., Boehler, T. & Debatin, K.M. TRAIL/Apo-2-ligand-induced apoptosis in human T cells. Eur. J. Immunol. 28, 143–152 (1998).

    Article  CAS  Google Scholar 

  19. Mariani, S.M. & Krammer, P.H. Differential regulation of TRAIL and CD95 ligand in transformed cells of the T and B lymphocyte lineage. Eur. J. Immunol. 28, 973–982 (1998).

    Article  CAS  Google Scholar 

  20. Walczak, H. et al. Tumoricidal activity of tumor necrosis factor-related apoptosis-inducing ligand in vivo. Nat. Med. 5, 157–163 (1999).

    Article  CAS  Google Scholar 

  21. Ashkenazi, A. et al. Safety and antitumor activity of recombinant soluble Apo2 ligand. J. Clin. Invest. 104, 155–162 (1999).

    Article  CAS  Google Scholar 

  22. Jo, M. et al. Apoptosis induced in normal human hepatocytes by tumor necrosis factor-related apoptosis-inducing ligand. Nat. Med. 6, 564–567 (2000).

    Article  CAS  Google Scholar 

  23. Simon, A.K. et al. Tumor necrosis factor-related apoptosis-inducing ligand in T cell development: sensitivity of human thymocytes. Proc. Natl. Acad. Sci. USA 98, 5158–5163 (2001).

    Article  CAS  Google Scholar 

  24. Martin-Villalba, A. et al. CD95 ligand (Fas-L/APO-1L) and tumor necrosis factor-related apoptosis-inducing ligand mediate ischemia-induced apoptosis in neurons. J. Neurosci. 19, 3809–3817 (1999).

    Article  CAS  Google Scholar 

  25. Sedger, L.M. et al. Characterization of the in vivo function of TNF-α-related apoptosis-inducing ligand, TRAIL/Apo2L, using TRAIL/Apo2L gene-deficient mice. Eur. J. Immunol. 32, 2246–2254 (2002).

    Article  CAS  Google Scholar 

  26. Cretney, E. et al. Increased susceptibility to tumor initiation and metastasis in TNF-related apoptosis-inducing ligand-deficient mice. J. Immunol. 168, 1356–1361 (2002).

    Article  CAS  Google Scholar 

  27. Song, K. et al. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is an inhibitor of autoimmune inflammation and cell cycle progression. J. Exp. Med. 191, 1095–1104 (2000).

    Article  CAS  Google Scholar 

  28. Zhang, Y. et al. In situ β cell death promotes priming of diabetogenic CD8 T lymphocytes. J. Immunol. 168, 1466–1472 (2002).

    Article  CAS  Google Scholar 

  29. Horwitz, M.S., Ilic, A., Fine, C., Rodriguez, E. & Sarvetnick, N. Presented antigen from damaged pancreatic β cells activates autoreactive T cells in virus-mediated autoimmune diabetes. J. Clin. Invest. 109, 79–87 (2002).

    Article  CAS  Google Scholar 

  30. Pechhold, K. et al. Low dose streptozotocin-induced diabetes in rat insulin promoter-mCD80-transgenic mice is T cell autoantigen-specific and CD28 dependent. J. Immunol. 166, 2531–2539 (2001).

    Article  CAS  Google Scholar 

  31. Woodland, D.L., Happ, M.P., Gollob, K.J. & Palmer, E. An endogenous retrovirus mediating deletion of α β T cells? Nature 349, 529–530 (1991).

    Article  CAS  Google Scholar 

  32. Tomonari, K., Fairchild, S. & Rosenwasser, O.A. Influence of viral superantigens on V β- and V α-specific positive and negative selection. Immunol. Rev. 131, 131–168 (1993).

    Article  CAS  Google Scholar 

  33. Yui, K. et al. Molecular and functional properties of novel T cell subsets in C3H- gld/gld and nude mice. Implications for thymic and extrathymic maturation. Immunol. Rev. 104, 121–155 (1988).

    Article  CAS  Google Scholar 

  34. Castro, J.E. et al. Fas modulation of apoptosis during negative selection of thymocytes. Immunity 5, 617–627 (1996).

    Article  CAS  Google Scholar 

  35. Muller, K.P., Mariani, S.M., Matiba, B., Kyewski, B. & Krammer, P.H. Clonal deletion of major histocompatibility complex class I-restricted CD4+CD8+ thymocytes in vitro is independent of the CD95 (APO-1/Fas) ligand. Eur. J. Immunol. 25, 2996–2999 (1995).

    Article  CAS  Google Scholar 

  36. Sytwu, H.K., Liblau, R.S. & McDevitt, H.O. The roles of Fas/APO-1 (CD95) and TNF in antigen-induced programmed cell death in T cell receptor transgenic mice. Immunity 5, 17–30 (1996).

    Article  CAS  Google Scholar 

  37. Page, D.M., Roberts, E.M., Peschon, J.J. & Hedrick, S.M. TNF receptor-deficient mice reveal striking differences between several models of thymocyte negative selection. J. Immunol. 160, 120–133 (1998).

    CAS  PubMed  Google Scholar 

  38. Nitsch, R. et al. Human brain-cell death induced by tumour-necrosis-factor-related apoptosis-inducing ligand (TRAIL). Lancet 356, 827–828 (2000).

    Article  CAS  Google Scholar 

  39. Green, D.R. & Reed, J.C. Mitochondria and apoptosis. Science 281, 1309–1312 (1998).

    Article  CAS  Google Scholar 

  40. Zhang, J., Cado, D., Chen, A., Kabra, N.H. & Winoto, A. Fas-mediated apoptosis and activation-induced T-cell proliferation are defective in mice lacking FADD/Mort1. Nature 392, 296–300 (1998).

    Article  CAS  Google Scholar 

  41. Kuida, K. et al. Reduced apoptosis and cytochrome c-mediated caspase activation in mice lacking caspase 9. Cell 94, 325–337 (1998).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  43. Newton, K., Harris, A.W., Bath, M.L., Smith, K.G. & 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 

  44. 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 

  45. Bouillet, P. et al. BH3-only Bcl-2 family member Bim is required for apoptosis of autoreactive thymocytes. Nature 415, 922–926 (2002).

    Article  CAS  Google Scholar 

  46. 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 

  47. 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 

  48. Lunemann, J.D. et al. Death ligand TRAIL induces no apoptosis but inhibits activation of human (auto)antigen-specific T cells. J. Immunol. 168, 4881–4888 (2002).

    Article  CAS  Google Scholar 

  49. Chaudhary, P.M. et al. Death receptor 5, a new member of the TNFR family, and DR4 induce FADD-dependent apoptosis and activate the NF-κB pathway. Immunity 7, 821–830 (1997).

    Article  CAS  Google Scholar 

  50. Hu, W.H., Johnson, H. & Shu, H.B. Tumor necrosis factor-related apoptosis-inducing ligand receptors signal NF-κB and JNK activation and apoptosis through distinct pathways. J. Biol. Chem. 274, 30603–30610 (1999).

    Article  CAS  Google Scholar 

  51. Lin, Y. et al. The death domain kinase RIP is essential for TRAIL (Apo2L)-induced activation of IκB kinase and c-Jun N-terminal kinase. Mol. Cell. Biol. 20, 6638–6645 (2000).

    Article  CAS  Google Scholar 

  52. Kumar-Sinha, C., Varambally, S., Sreekumar, A. & Chinnaiyan, A.M. Molecular cross-talk between the TRAIL and interferon signaling pathways. J. Biol. Chem. 277, 575–585 (2002).

    Article  CAS  Google Scholar 

  53. Chen, Y., Inobe, J.-i. & Weiner, H.L. Induction of oral tolerance to MBP in CD8-depleted mice. J. Immunol. 155, 910–916 (1995).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank J. Sun, E. Rowell, L.-Y. Xu, P. Wang and G. Tsabary for technical assistance, M. I. Greene and B. Hilliard for discussions. Supported by grants from the National Institutes of Health (AI50059, NS40188 and NS40447 to Y.H.C.).

*Note: In the version of this article initially published online, this paper contained a misspelling of the first author's name, which should have been spelled Salah-Eddine Lamhamedi-Cherradi. This mistake has been corrected in the HTML version and print versions of the article. We regret the error.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Youhai H. Chen.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lamhamedi-Cherradi, SE., Zheng, SJ., Maguschak, K. et al. Defective thymocyte apoptosis and accelerated autoimmune diseases in TRAIL−/− mice. Nat Immunol 4, 255–260 (2003). https://doi.org/10.1038/ni894

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni894

This article is cited by

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