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.