The transcriptional events that control T cell tolerance to peripheral self Ags are still unknown. In this study, we analyzed the regulation of AP-1-and NF-κB-mediated transcription during in vivo induction of tolerance to a self Ag expressed exclusively on hepatocytes. Naive CD8+ Désiré (Des)+ T cells isolated from the Des TCR-transgenic mice that are specific for the H-2K b class I Ag were transferred into Alb-K b-transgenic mice that express the H-2K b Ag on hepatocytes only. Tolerance develops in these mice. We found that the self-reactive CD8+ Des+ T cells were transiently activated, then became unresponsive and were further deleted. In contrast to CD8+ Des+ T cells activated in vivo with APCs, which express high AP-1 and high NF-κB transcriptional activity, the unresponsive CD8+ Des+ T cells expressed no AP-1 and only weak NF-κB transcriptional activity. The differences in NF-κB transcriptional activity correlated with the generation of distinct NF-κB complexes. Indeed, in vivo primed T cells predominantly express p50/p50 and p65/p50 dimers, whereas these p50-containing complexes are barely detectable in tolerant T cells that express p65-and c-Rel-containing complexes. These observations suggest that fine regulation of NF-κB complex formation may determine T cell fate.