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-kappa B-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-kappa B transcriptional activity, the unresponsive CD8(+)Des(+) T cells expressed no AP-1 and only weak NF-kappa B transcriptional activity. The differences in NF-kappa B transcriptional activity correlated with the generation of distinct NF-kappa B 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-kappa B complex formation may determine T cell fate.