Tuesday, April 23, 2024
4/23/2024
PROJECT SUMMARY The signaling pathways involving phosphoinositide-3-kinases (PI3Ks) are highly conserved and tightly regulated to influence the activation, proliferation, and survival of all cell types. PI3K signaling plays a major role in T cell responses to antigen due to its position directly downstream of T cell receptor (TCR)/CD28 ligation. Our lab has recently shown that the cell surface protein TrIP (Transmembrane Inhibitor of PI3K, gene name: Pik3ip1) has a distinctly high expression on T cells and is capable of downregulating PI3K signaling in CD4+ T cells, acting as a negative regulator of T cell immune responses. These studies revealed that CD4+ T cells lacking TrIP expression exhibit a more Th1 inflammatory phenotype compared to WT controls both in vivo and in vitro. These data have led us to propose that TrIP restricts the inflammatory activity of CD8+ T cells, and that targeting/knockout of this negative regulator may promote anti-tumor immunity. I have already obtained preliminary data demonstrating that CD8+ T cell-specific TrIP knockout mice (TrIPfl/flE8icre) are resistant to growth of syngeneic tumors. In addition to increased tumor resistance, we have also found that tumors harvested from our TrIPfl/flE8icre knockout mice contain twice as many infiltrating T cells compared to their WT counterparts. We also found that CD8+ T cells were the main drivers of this increased T cell infiltration, as their frequency was double that of the CD4+ population. These preliminary data are the basis of our proposal aimed at further elucidating cell-intrinsic effects of TrIP activity in CD8+ T cells, including its impact on antitumor immunity. These studies will not only improve our understanding of TrIP as a negative immune regulator, but also inform on the potential for TrIP as a future immunotherapeutic target.
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