Death receptor-induced apoptosis signalling - essential guardian against autoimmune disease
© Strasser et al.; licensee BioMed Central Ltd. 2012
Published: 29 February 2012
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.
- 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 CentralPubMedGoogle Scholar
- 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.PubMed CentralView ArticlePubMedGoogle Scholar
- 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.PubMed CentralView ArticlePubMedGoogle Scholar
- 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.View ArticlePubMedGoogle Scholar
- 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.PubMed CentralView ArticlePubMedGoogle Scholar
- 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.PubMed CentralView ArticlePubMedGoogle Scholar
- 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.PubMed CentralView ArticlePubMedGoogle Scholar
- 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.View ArticleGoogle Scholar
- 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.PubMed CentralView ArticlePubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.