The major pathway of T cell development in the thymus proceeds in an orderly fashion from the entry of blood-borne stem cells to the export of mature, antigen responsive CD4+ and CD8+ T cells. In past years, this grant has been concerned with unraveling how the T cell receptor (TCR) repertoire is selected in the thymus by interaction of newly generated receptors with self MHC-self peptide complexes expressed in the thymus. It is apparent that signals from sources other than TCR-MHC interaction are critically involved in controlling T cell differentiation. Immature thymocytes are extremely sensitive to apoptosis induced by glucocorticoids, and there is evidence that this signaling pathway and TCR signals intersect. Notch-1 is a transmembrane receptor that transmits signals directly to the nucleus following productive interaction with membrane-bound ligands. In other invertebrate and vertebrate developmental systems, Notch signaling has been implicated in determining lineage choice. Recently, evidence has been presented or Notch-1 signaling involvement in the ab versus-gd, and CD8+-versus-CD4+ lineage choice in the thymus. In a number of T cell lines, constitutively active Notch-1 induces resistance to glucocorticoid-induced cell cycle arrest and apoptosis. The goal of this project is to identify genes that are turned on or off in T cells following activation of the Notch-1 signaling pathway and to determine how Notch-1 signaling affects the process of thymocyte differentiation. An integrated series of experiments in cell lines and in transgenic animals will be performed to get at these questions. It is hoped that the work will provide a better understanding of the integration of signals from the TCR, the glucocorticoid receptor, and Notch that developing T cells receive.
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