Inefficient ZAP-70 phosphorylation and decreased thymic selection in vivo result from inhibition of NF-kappa B/Rel

Signaling from the TCR regulates T lymphoid survival, deletion by apoptosis , and selective clonal expansion. One set of signaling pathways activated d uring thymic selection leads to degradation of a cytosolic retention protei n, the inhibitor of kappaB (I kappaB)alpha, followed by nuclear translocati on of the NF-kappaB/ReI family of transcription factors. It has been found previously that NF-kappaB proteins mediate a pathway signaling the survival of mature T cells and protection of thymocytes against TNT-induced apoptos is. In contrast, we show in this study that a transgenic inhibitor of NF-ka ppaB/ReI signaling interferes with the negative selection of immature thymo cytes by endogenous MHC ligands in vivo. Positive selection of the H-Y TCR also was diminished. This attenuation of thymic selection efficiency was as sociated with decreased ZAP-70 phosphorylation and TCR signaling of CD69 in duction. These findings demonstrate that the NF-kappaB transcriptional path way plays an important role in normal processes of clonal deletion and they indicate that the NF-kappaB/I kappaB axis can regulate the efficiency of T CR signaling.