Fas-mediated apoptosis and activation-induced T-cell proliferation are defective in mice lacking FADD/Mort1.
Programmed cell death, or apoptosis, is important in homeostasis of the immune system: for example, non-functional or autoreactive lymphocytes are eliminated through apoptosis. One member of the tumour necrosis factor receptor (TNFR) family, Fas (also known as CD95 or Apo-1), can trigger cell death and is essential for lymphocyte homeostasis. FADD/Mort1 is a Fas-associated protein that is thought to mediate apoptosis by recruiting the protease caspase-8. A dominant-negative mutant of FADD inhibits apoptosis initiated by Fas and other TNFR family members. Other proteins, notably Daxx, also bind Fas and presumably mediate a FADD-independent apoptotic pathway. Here we investigate the role of FADD in vivo by generating FADD-deficient mice. As homozygous mice die in utero, we generated FADD-/- embryonic stem cells and FADD-/- chimaeras in a background devoid of the recombination activating gene RAG-1, which activates rearrangement of the immunoglobulin and T-cell receptor genes. We found that thymocyte subpopulations were apparently normal in newborn chimaeras. Fas-induced apoptosis was completely blocked, indicating that there are no redundant Fas apoptotic pathways. As these mice age, their thymocytes decrease to an undetectable level, although peripheral T cells are present in all older FADD-/- chimaeras. Unexpectedly, activation-induced proliferation is impaired in these FADD-/- T cells, despite production of the cytokine interleukin (IL)-2. These results and the similarities between FADD-/- mice and mice lacking the beta-subunit of the IL-2 receptor suggest that there is an unexpected connection between cell proliferation and apoptosis.
Zhang
J
J
Department of Molecular and Cell Biology, University of California at Berkeley, 94720-3200, USA.
Cado
D
D
Chen
A
A
Kabra
N H
NH
Winoto
A
A
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017209:Apoptosis; D001402:B-Lymphocytes / Q000166:cytology; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D002455:Cell Division; D004268:DNA-Binding Proteins / Q000235:genetics; D053200:Fas-Associated Death Domain Protein; D005313:Fetal Death; D005434:Flow Cytometry; D018398:Homeodomain Proteins; D007376:Interleukin-2 / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D015183:Restriction Mapping; D013234:Stem Cells; D013601:T-Lymphocytes / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology; D018183:Transplantation Chimera; D019014:fas Receptor / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C505534:Fadd protein, mouse; D053200:Fas-Associated Death Domain Protein; D018398:Homeodomain Proteins; D007376:Interleukin-2; D019014:fas Receptor; C064658:RAG-1 protein