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Measuring Composition of CD95 Death-Inducing Signaling Complex and Processing of Procaspase-8 in this Complex
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Participation of FLIP, RIP and Bcl-x(L) in Fas-mediated T-cell death

M Djerbi1, M M Malinowski, H Yagita

  • 1Department of Immunology, The Wenner-Gren Institute, University of Stockholm, Stockholm, Sweden.

Scandinavian Journal of Immunology
|September 14, 2007
PubMed

Insights

Mice models revealed that while caspase-dependent pathways are key in Fas-mediated cell death, uncharacterized Fas receptor pathways significantly contribute to autoimmune diseases like lymphoproliferative syndrome.

Area of Science:

  • Immunology
  • Cell Death Signaling
  • Molecular Biology

Background:

  • Fas receptor (also known as CD95 or APO-1) mediates apoptosis, a critical process in immune system regulation.
  • Alternative cell death pathways, including mitochondrial and RIPK1-mediated routes, are implicated in Fas signaling beyond the canonical pathway.
  • Dysregulation of Fas signaling is linked to lymphoproliferative and autoimmune disorders, such as autoimmune lymphoproliferative syndrome (ALPS).

Purpose of the Study:

  • To elucidate the distinct contributions of various Fas signaling pathways to Fas-mediated cell death.
  • To investigate the roles of FLICE-inhibitory protein (FLIP(L)), Bcl-x(L), and a dominant-negative RIP kinase (RIPDeltakin) in regulating Fas-induced apoptosis.
  • To assess the involvement of these pathways in the pathogenesis of autoimmune diseases.

Main Methods:

  • Generation of transgenic mice overexpressing FLIP(L), Bcl-x(L), or RIPDeltakin using retroviral gene transfer into hematopoietic stem cells.
  • Analysis of hematopoietic development, thymic deletion, T cell populations, and autoimmune phenotypes in the generated mouse models.
  • Assessment of Fas-mediated cell death in activated and resting CD4(+) and CD8(+) T cells using the developed mouse models.

Main Results:

  • Mice overexpressing FLIP(L), Bcl-x(L), or RIPDeltakin did not exhibit significant developmental abnormalities or autoimmunity.
  • Fas-mediated death of activated T cells was primarily caspase-dependent, with minor contributions from Bcl-x(L) or RIPDeltakin pathways.
  • Fas-mediated death of resting T cells was largely caspase-dependent but only partially inhibited by FLIP(L); Bcl-x(L) and RIPDeltakin offered partial protection to CD8(+) T cells.

Conclusions:

  • Fas-mediated T cell death involves complex interplay between caspase-dependent and independent pathways.
  • FLIP(L) plays a dominant role in inhibiting Fas-mediated apoptosis of activated T cells.
  • Uncharacterized signaling pathways originating from the Fas receptor are critical drivers of lymphoproliferative and autoimmune diseases observed in lpr mice and ALPS patients.

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