Impaired NF-κB activation in T cells permits tolerance to primary heart allografts and to secondary donor skin grafts

Abstract

T-cell activation is essential for acute allograft rejection. However, the biochemical signaling pathways used by T cells mediating rejection have not been extensively investigated. In vitro, T-cell activation is associated with nuclear translocation of specific transcription factors that regulate expression of genes critical for T-cell function. Given the central role of NF-κB in T-cell activation In vitro, we examined its role in the acute rejection of skin and cardiac allografts using mice with defective NF-κB translocation in T cells due to the presence of a super repressor IκBα transgene. T-cell-intrinsic NF-κB activation was required for cardiac but not skin allograft rejection, suggesting differential T-cell priming by the two tissues. Strikingly, priming with heart allografts induced complete acceptance of subsequently transplanted donor skin grafts, indicating that impaired NF-κB activation in T cells facilitates the induction of donorspecific tolerance to highly immunogenic tissues. These data suggest the biochemical pathways necessary for allograft rejection vary, based on the antigen and the context in which it is presented, and that inhibition of T-cell-intrinsic NF-κB activation during allogeneic priming may represent a novel strategy whereby tolerance to transplanted organs can be achieved.