The Notch family of proteins is comprised of four highly conserved membrane receptors. At least three of these proteins, Notch1, Notch2 and Notch3, are expressed at various times during lymphoid development. Under normal circumstances, Notch expression directs the development of the T cell lineage. Aberrant Notch expression results in T lymphoid tumors suggesting the expression of this gene can participate in oncogenic transformation. Preliminary data presented in this proposal demonstrate that signaling via the T cell receptor (TCR) induces both the expression and activation of a Notch-dependent signaling pathway. To determine the consequences of TCR-induced Notch expression in peripheral T cells, mice expressing an antisense Notch construct (Notch AS) were examined. Additionally pharmacological inhibitors of Notch activation were used to inhibit Notch activity. Using these two approaches, data is presented demonstrating that Notch activation is required for TCR-induced proliferation of both CD4 and CD8 subsets of T cells. From our preliminary data, we hypothesize that Notch signaling in peripheral T cells has several important consequences. First of all, in both CD4 and CD8 T cells, Notch signaling drives cytokine production and proliferation. We also suggest a specific signaling pathway through the TCR that regulates Notch expression and results in activation of NF-kB. We propose that Notch is required for both NF-kB activity and IFN-gamma production in CD8 T cells and suggest that NF-kB may directly regulate IFN-gamma production in CD8 cells. We also propose that Notch is required for Th1 function either by participating in the polarization of naive CD4 cells into Th1 or by driving Th1 cytokine production following polarization. Our data also support a role for differential Notch activation in the CD4+, CD25- subset versus the CD4+, CD25+ subset and suggest that Notch expression in these important CD4 T cell subsets may have functional consequences. Lastly we propose that Notch may regulate cell cycle progression in T cells through activation of cyclin D2 and D3.
Four aims are proposed to address the hypotheses presented.
Aim I asks how TCR signaling regulates Notch activation.
Aim II asks how Notch regulates NF-kB.
Aim III examines the functional consequences of Notch activation in peripheral T cells and Aim IV asks how Notch regulates cell cycle progression in T cells.
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