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

Signaling from the TCR regulates T lymphoid survival, deletion by apoptosis, and selective clonal expansion. One set of signaling pathways activated during thymic selection leads to degradation of a cytosolic retention protein, the inhibitor of κB (IκB)α, followed by nuclear translocation of the NF-κB/Rel family of transcription factors. It has been found previously that NF-κB proteins mediate a pathway signaling the survival of mature T cells and protection of thymocytes against TNF-induced apoptosis. In contrast, we show in this study that a transgenic inhibitor of NF-κB/Rel signaling interferes with the negative selection of immature thymocytes by endogenous MHC ligands in vivo. Positive selection of the H-Y TCR also was diminished. This attenuation of thymic selection efficiency was associated with decreased ZAP-70 phosphorylation and TCR signaling of CD69 induction. These findings demonstrate that the NF-κB transcriptional pathway plays an important role in normal processes of clonal deletion and they indicate that the NF-κB/IκB axis can regulate the efficiency of TCR signaling.