Coordinate Regulation of TCR signaling, Notch, and Gata3 in T Cell Development (138.27)

Abstract

Abstract The transcription factors, Notch and Gata3, are both involved in the intrathymic development of CD4 lineage T cells. It has been proposed that Gata3 is critical in CD4 T cell maturation after lineage commitment. To the contrary, we find that disruption of the Gata3 gene re-directs a fraction of MHC II-restricted thymocytes to the CD8 lineage. Moreover, Gata3 binds regulatory regions of the ThPOK (Zbtb7b) gene in vivo and is required for the ThPOK expression that enforces CD4 lineage commitment (Nature Immunol. 9:1122). Collectively, these findings place Gata3 developmentally upstream of the CD4/CD8 lineage decision and raise the question of how Gata3 itself is regulated. Our data and that of others suggest that Gata3 expression is regulated by TCR signaling, but Gata3 can also promote TCR signaling/expression. Therefore, Gata3 may operate in a self-reinforcing feedback loop during positive selection to achieve the levels of TCR signaling required for ThPOK induction and CD4 lineage commitment. In the differentiation of peripheral Th2 cells, Gata3 transcription can be regulated by Notch. We find that Notch and Gata3 promote TCR signal transduction prior to positive selection, as well as the selection/maturation of CD4/CD8 T lineages. Thus, we have designed genetic and expression studies to investigate whether Notch regulates Gata3 in thymocytes. Intramural Research Program of the National Institute of Allergy and Infectious Diseases.