Skip to main content

Death receptor-induced apoptosis signalling - essential guardian against autoimmune disease

The FasL/Fas system is critical for deletion of autoreactive and antigen-activated T and B cells. Accordingly, mutations in these proteins result in lymphadenopathy and autoimmunity in gld and lpr mutant mice, which lack functional FasL or Fas, respectively. Upon antigenic stimulation of T cells, FasL is sythesised, directed to and stored in secretory lysosomes followed by extrusion at the immunological synapse where it is rapidly downregulated by a metalloprotease, shedding the extracellular portion (sFasL) to prevent non-specific killing. It is unclear whether the pathology observed in gld mutant mice is due to the loss of the membrane-bound or the secreted form of FasL or both.

We have produced a panel of mutant FasL knock-in mice to address this question. In the first mutant strain the cytoplasmic and trans-membrane domains of FasL were replaced with the signal peptide from G-CSF. Activated T cells from these mutant mice can produce cytoplasmic but no membrane bound FasL and, interestingly, they are defective in FasL-mediated cytotoxic function and undergo significantly less activation-induced cell death upon re-stimulation with anti-CD3 antibodies than wt T cells. The extent of these defects is similar to that seen in FasL mutant gld T cells. With age these FasL mutant knock-in mice develop lymphadenopathy and splenomegaly and CD3+B220+CD4-CD8- T cells accumulate, similarly to what has been observed in gld and lpr mutant mice. In contrast to gld mice, the FasL mutant knock-in mice on the C57BL/6 background develop haemopoietic tumours and reticular cell sarcomas, suggesting that while membrane-bound FasL is the guardian against autoimmunity, secreted FasL may play a critical role in tissue damage and tumour suppression.

References

  1. Strasser A, Harris AW, Huang DCS, Krammer PH, Cory S: Bcl-2 and Fas/APO-1 regulate distinct pathways to lymphocyte apoptosis. EMBO J. 1995, 14: 6136-6147.

    PubMed Central  CAS  PubMed  Google Scholar 

  2. Newton K, Harris AW, Bath ML, Smith KGC, Strasser A: A dominant interfering mutant of FADD/MORT1 enhances deletion of autoreactive thymocytes and inhibits proliferation of mature T lymphocytes. EMBO J. 1998, 17: 706-718. 10.1093/emboj/17.3.706.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Huang DCS, Hahne M, Schroeter M, Frei K, Fontana A, Villunger A, Newton K, Tschopp J, Strasser A: Activation of Fas by FasL induces apoptosis by a mechanism that cannot be blocked by Bcl-2 or Bcl-xL. Proc Natl Acad Sci USA. 1999, 96: 14871-14876. 10.1073/pnas.96.26.14871.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. Kaufmann T, Tai L, Ekert PG, Huang DCS, Norris F, Lindemann RK, Johnstone RW, Dixit VM, Strasser A: The pro-apoptotic BH3-only protein Bid is dispensable for DNA damage- and replicative stress-induced apoptosis or cell cycle arrest. Cell. 2007, 129: 423-433. 10.1016/j.cell.2007.03.017.

    Article  CAS  PubMed  Google Scholar 

  5. Hughes PD, Belz GT, Fortner KA, Budd RC, Strasser A, Bouillet P: Fas and Bim cooperate in shutdown of chronic immune responses and prevention of autoimmunity. Immunity. 2008, 28: 197-205. 10.1016/j.immuni.2007.12.017.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Kaufmann T, Jost P, Pellegrini M, Puthalakath H, Gugasyan R, Gerondakis S, Cretney E, Smyth M, Silke J, Hakem R, Bouillet P, Mak T, Dixit VM, Strasser A: Fatal hepatitis mediated by TNFa requires caspase-8 and involves the BH3-only proteins Bid and Bim. Immunity. 2009, 30: 56-66. 10.1016/j.immuni.2008.10.017.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Jost PJ, Grabow S, Gray D, McKenzie MD, Nachbur U, Huang DCS, Bouillet P, Thomas HE, Borner C, Silke J, Strasser A, Kaufmann T: XIAP acts as a switch between type I and type II Fas-induced apoptosis signalling. Nature. 2009, 460: 1035-1039. 10.1038/nature08229.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. O'Reilly LA, Tai L, Lee L, Kruse EA, Grabow S, Fairlie WD, Haynes NM, Tarlinton DM, Zhang J-G, Belz GT, Smyth MJ, Bouillet P, Robb L, Strasser A: Membrane-bound but not secreted Fas ligand is essential for Fas-induced apoptosis and prevention of autoimmunity and cancer. Nature. 2009, 461: 659-663. 10.1038/nature08402.

    Article  Google Scholar 

  9. Strasser A, Jost P, Nagata S: The many roles of FasL-Fas signaling in the immune system. Immunity. 2009, 30: 180-192. 10.1016/j.immuni.2009.01.001.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Andreas Strasser.

Rights and permissions

This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Cite this article

Strasser, A., O'Reilly, L.A., Jost, P. et al. Death receptor-induced apoptosis signalling - essential guardian against autoimmune disease. Arthritis Res Ther 14 (Suppl 1), O8 (2012). https://doi.org/10.1186/ar3563

Download citation

  • Published:

  • DOI: https://doi.org/10.1186/ar3563

Keywords