Molecular Basis for gamma/delta T Lineage Specification

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DESCRIPTION (provided by applicant): Both the commitment of progenitors to the γδ lineage and specification of their effector fates occurs during development in the thymus; however, our understanding of the developmental cues controlling these fate decisions remains incomplete. Accumulating evidence suggests that both γδ lineage commitment and effector fate are influenced by differences in T cell receptor (TCR) signal strength. The differences in TCR signal strength influence fate by inducing Id3, an antagonist of E protein DNA binding. While E proteins clearly play a central role, their influence on developmental outcomes is almost certainly modulated by additional transcription factors and the extracellular signals that control their expression and function. Accordingly, these fate decisions are too complex to be understood by focusing on one gene or pathway and so require the comprehensive, network-based approach pioneered by Murre. The overall goal of this program is to determine how γδ TCR signals of varying intensities are generated and understand the role that the resultant alterations in E protein activity and cooperating DNA-binding proteins play in influencing lineage and γδ effector fate. Gaining a comprehensive understanding of such a multifaceted developmental process is beyond the scope of any individual laboratory, as it requires facility with numerous experimental approaches to manipulate fate-determining cues and assess their effect on fate, both functionally and molecularly, in vitro and in vivo. The investigators comprising this program possess the necessary distinct, yet complementary, skills to do so. The Wiest lab (Project 1) has generated in vivo and in vitro models in which developmental fates can be manipulated by altering TCR signal intensity. Dr. Zuniga-Pflucker (Project 3) has established elegant in vitro and in vivo systems in which Notch and cytokine input can be manipulated to assess the impact on effector fate. Drs. Zhuang (Project 2) and Murre (Project 4) are experts in the genetic and molecular analysis of E proteins and their Id family antagonists. Finally, Dr. Murre (Genomics Core) will utilize his novel bioinformatic approach to assist all projects in molecularly defining critical milestones in γδ development by assembling global regulatory networks assembled around E protein targets. Collectively, these efforts promise to move the field forward by comprehensively defining the processes controlling γδ lineage commitment and effector fate from extracellular signals to the network of targets in the nucleus.