TCF-1 regulates NKG2D expression on CD8 T cells during anti-tumor responses

Cancer immunotherapy relies on improving T cell effector functions against malignancies, but despite the identification of several key transcription factors (TFs), the biological functions of these TFs are not entirely understood. We developed and utilized a novel, clinically relevant murine model to dissect the functional properties of crucial T cell transcription factors during antitumor responses. Our data showed that TCF-1 suppresses surface NKG2D expression on naïve and activated CD8 T cells via key transcriptional factors Eomes and T-bet.Using both in vitro and in vivo models, we uncovered how TCF-1 regulatescritical molecules responsible for peripheral CD8 T cell effector functions. Finally, our unique genetic and molecular approaches proved that TCF-1 also differentially regulates essential kinases. These kinases, including LCK, LAT, ITK, PLC-g1, P65, ERKI/II, and JAK/STATs, are required for peripheral CD8 T cell persistent function during alloimmunity. Overall, our molecular and bioinformatics data demonstrate the mechanism by which TCF-1 modulatedseveral critical aspects of T cell function during CD8 T cell response to cancer.