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Inefficient ZAP-70 Phosphorylation and Decreased Thymic Selection In Vivo Result from Inhibition of NF-B/Rel¹

Ana L. Mora^*, Sarah Stanley^*, Wade Armistead^*, Andrew C. Chan and Mark Boothby^2,*

^* Department of Microbiology and Immunology, Vanderbilt University Medical School, Nashville, TN 37232; and Washington University School of Medicine, St. Louis, MO 63110

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 B (IB), followed by nuclear translocation of the NF-B/Rel family of transcription factors. It has been found previously that NF-B 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-B/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-B transcriptional pathway plays an important role in normal processes of clonal deletion and they indicate that the NF-B/IB axis can regulate the efficiency of TCR signaling.

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