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This article is part of the supplement: Proceedings of the 8th Global Arthritis Research Network (GARN) Meeting and 1st Bio-Rheumatology International Congress (BRIC)

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

Andreas Strasser1*, Lorraine A O'Reilly1, Philipp Jost1, Thomas Kaufmann1, Stephanie Grabow1, Elizabeth Kruse1, Lin Tai1, Mark Smyth2 and Philippe Bouillet1

Author Affiliations

1 The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia

2 The Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, Victoria 3000, Australia

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Arthritis Research & Therapy 2012, 14(Suppl 1):O8  doi:10.1186/ar3563

The electronic version of this article is the complete one and can be found online at:

Published:9 February 2012

© 2012 Strasser et al.; licensee BioMed Central Ltd.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Oral presentation

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.


  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 Abstract | PubMed Central Full Text OpenURL

  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. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  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. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  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. PubMed Abstract | Publisher Full Text OpenURL

  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. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  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. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  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. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  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. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  9. Strasser A, Jost P, Nagata S: The many roles of FasL-Fas signaling in the immune system.

    Immunity 2009, 30:180-192. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL