Essential roles of the Fas-associated death domain in autoimmune encephalomyelitis.
The Fas-associated death domain (FADD) protein mediates apoptosis by coupling death receptors with the caspase cascade. Paradoxically, it also promotes cell mitosis through its C-terminal region. Apoptosis and mitosis are opposing processes that can have radically different consequences. To determine which of the FADD effects prevails in T cell-mediated autoimmune diseases, we studied myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis (EAE) using mice that express a dominant-negative FADD (FADD-DN) transgene in the T cell lineage. We found that FADD blockade in T cells prevented the development of autoimmune encephalomyelitis and inhibited both Th1 and Th2 type responses. Myelin oligodendrocyte glycoprotein-specific T cell proliferation was also dramatically reduced in FADD-DN mice despite the resistance of T cells to activation-induced cell death. These results indicate that although FADD expressed by T cells is involved in regulating both mitosis and apoptosis, its effect on mitosis prevails in EAE, and that strategies inhibiting FADD functions in T cells could be effective in preventing the disease.
Sun
Jing
J
Department of Pathology and Laboratory Medicine, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Hilliard
Brendan
B
Xu
Lingyun
L
Chen
Youhai H
YH
D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000378:metabolism*; D053200:Fas-Associated Death Domain Protein; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008938:Mitosis; D017434:Protein Structure, Tertiary; D013601:T-Lymphocytes / Q000276:immunology
D048868:Adaptor Proteins, Signal Transducing; C505534:Fadd protein, mouse; D053200:Fas-Associated Death Domain Protein