Fas mediates cardiac allograft acceptance in mice with impaired T-cell-intrinsic NF-kappaB signaling.
The transcription factor NF-kappaB is critical for T-cell activation and survival. We have shown that mice expressing a T-cell-restricted NF-kappaB superrepressor (IkappaBalphaDeltaN-Tg) permanently accept heart but not skin allografts. Overexpression of the prosurvival factor Bcl-x(L) in T cells restored heart rejection, suggesting that graft acceptance in IkappaBalphaDeltaN-Tg mice was attributable to deletion of alloreactive T cells.In vitro, the increased death of IkappaBalphaDeltaN-Tg T cells upon TCR stimulation when compared with wildtype T cells was mostly because of Fas/FasL interaction. Similarly, Fas played a key role in cardiac allograft acceptance by IkappaBalphaDeltaN-Tg mice as both genetic and antibody-mediated inhibition of Fas-signaling restored cardiac allograft rejection. Rejection correlated with graft infiltration by T cells and splenic production of IFN-gamma upon allostimulation. These results indicate that T-cell inhibition of NF-kappaB results in cardiac allograft acceptance because of increased susceptibility to Fas-mediated cell death.
Molinero
Luciana Lorena
LL
Department of Medicine, Section of Rheumatology, The University of Chicago, 5841 S. Maryland Ave., Chicago, IL 60637, USA. lmoliner@medicine.bsd.uchicago.edu
Wang
Ying
Y
Zhou
Ping
P
Yagita
Hideo
H
Alegre
Maria-Luisa
ML
D000818:Animals; D017209:Apoptosis; D053222:Fas Ligand Protein / Q000276:immunology; D006084:Graft Rejection / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology*; D020672:I-kappa B Proteins / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000502:physiology*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*; D014184:Transplantation, Homologous / Q000502:physiology; D019014:fas Receptor / Q000502:physiology*
D053222:Fas Ligand Protein; D020672:I-kappa B Proteins; D016328:NF-kappa B; D019014:fas Receptor