Transcriptional cascades in the CD4/CD8 lineage choice

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DESCRIPTION (provided by applicant): Thymocyte maturation involves a number of lineage decisions. The decision to become mature CD4+ helper T cells vs. CD8+ killer T cells is determined by the integration of signals received through T cell receptors and CD4 and CD8 coreceptors. The developmental fate receptor, Notch, has also been implicated in CD4 vs. CD8 lineage commitment. The interpretation of these integrated signals is the activation of transcription factors, which then orchestrate differential development of a common precursor, CD4+CD8+ thymocytes, into either helper or killer T cells. There are a number of candidate transcription factors with possible functions in lineage commitment and maturation. Their roles during thymocyte DP to SP transition and their subsequent transcriptional cascades will be directly addressed in this proposal along with methods of identifying more thymocyte developmental mediators. Aim 1: Evaluate the roles of transcription factors and mediators implicated in the CD4 vs. CD8 lineage decision by following their kinetics during the induction of CD4 or CD8 maturation in thymic organ cultures. Aim 2: Identify other TCR- and Notch-induced downstream mediators and targets by differential display and microarray analysis.