DESCRIPTION: (Applicant's Abstract): The two major functional classes of mature T cells, CD4+ helper T cells and CD8+ killer T cells, arise from a common precursor in the thymus. Understanding the mechanism by which a thymic precursor cell chooses between the CD4 or CD8 lineages is crucial to understanding how immune responses are generated and may improve our ability to manipulate immune responses in humans. The long-term goal of this project is to identify the molecular events that translate positive selection signals into the appropriate lineage choice. Recognition of MHC proteins guides the CD4/CD8 lineage choice and the CD4 and CD8 co-receptors participate in this process, but the molecular details remain poorly understood. Most recently, the Notch signaling pathway has been implicated as a player in the CD4 versus CD8 lineage decision, providing a new avenue for investigating this problem. The specific aims of this application are designed to link the Notch signaling pathway with MHC recognition during T cell development. The recent identification of an inhibitor of Notch called Numb, that appears to be regulated by MHC in the thymus, suggests a model in which MHC recognition regulates Numb, Numb regulates Notch, and Notch in turn regulates the CD4/CD8 lineage choice. Aims 1-3 focus on testing this model by investigating the timing of Numb regulation by MHC, the mechanism of Numb regulation, and the consequences of Numb mutations on the CD4/CD8 lineage choice. Aim 4 investigates the role of other potential Notch regulators, such as Notch ligands or Fringe, in the CD4/CD8 lineage choice.