Identifying the function of Notch1 in T-cell activation (121.1)

Abstract

Abstract The Notch receptor is activated by ligands that belong to the Delta or Jagged family. Ligand binding is followed by proteolytic cleavages resulting in the release of intra-cellular Notch which translocates to the nucleus and functions as a transcriptional activator. While the role of Notch in thymocyte maturation has been studied, the precise role of Notch in T-cell activation and cellular metabolism remains incompletely understood. Evidence from our lab has suggested that TCR mediated activation leads to the generation of active Notch and inhibition via Gamma Secretase Inhibitors (GSI) decreases T cell activation and proliferation. However, since GSI’s are known to have multiple substrates, whether such a decrease in activation is indeed dependent on Notch or is simply a GSI mediated effect needs to be examined. To determine the role of Notch in T cell activation we conditionally deleted Notch1 in peripheral T cells. Our data demonstrate that CD4 cells have reduced expression of activation markers accompanied by a decrease in IL-2 and IFN-Gamma secretion as well as impaired proliferation in the absence of Notch1. Notch1 was also required for polarization towards Th1. Furthermore, absence of Notch1 decreased pAkt-S473 implying reduced mTORC2 activity. Our data implicate the importance of Notch1 in T cell function. Future studies are aimed to delineate the role of non-canonical Notch1 signaling in T cells and how it may influence molecular pathways downstream of the TCR.