T CELL DIFFERENTIATION

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A major aim of this project is to identify the signals that control cell fate decisions in developing T cells. Our primary focus in the past year has been on the role of the T cell antigen receptor (TCR) and how it works together with other developmental cues to control maturation, proliferation, death, and lineage commitment. In these studies we have determined that: * The nature of the TCR signal (__ vs. __ in the _____ lineage choice and the involvement of CD4 vs. CD8 in the CD4/CD8 lineage decision) imposes a bias on the lineage choice. * Signals through the highly conserved, transmembrane receptor, Notch, also biases these lineage decisions. * A constitutively active form of Notch can override the bias normally imposed by the TCR signal, suggesting that the two signaling systems may act in concert to specify cell fate. * Cell-cell interactions between neighboring thymocytes influence __ versus __ T cell fate. * The expression of some TCR-associated signal transducing proteins are developmentally regulated in maturing T cells. * __ T cells require interactions with a self-protein, MHC, for maturation and survival (positive selection). If this interaction produces very strong signals inside the cell, cell death rather than maturation will occur (negative selection). Our results indicate that for those cells that survive, it is also the relative strength of the interaction that determines whether a cell will become a CD4 or CD8 T cell. * Once the lineage choice is made, additional mechanisms operate to insure that the appropriate T cell receptor is expressed in the appropriate lineage. * Whether a developing T cell is positively or negatively selected is affected by the quantity of MHC+peptide ligand and the cell type expressing the selecting ligand.