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

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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.

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Correspondence to Andreas Strasser.

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Keywords

  • Mutant Mouse
  • Antigenic Stimulation
  • Reticular Cell
  • Immunological Synapse
  • Secrete Form