TCF-7 is dispensable for anti-tumor response but required for persistent function of mature CD8 T cells

T Cell Factor-1, encoded by TCF-7, is a transcription factor that plays an essential role during T cell development and differentiation. In this manuscript we utilized a pre-clinical model provided evidence that TCF-7 is dispensable for the anti-tumor response, and that TCF-7 suppresses key transcriptional factors Eomes and T-bet and molecules responsible for peripheral CD8 T cell cytolytic function. We discovered that TCF-7 regulates NKG2D expression on naïve and activated mouse CD8 T cells, and that peripheral CD8 T cells from TCF-7 cKO utilize NKG2D to clear tumor cells. We also provide evidence that TCF-7 regulates key signaling molecules, including LCK, LAT, ITK, PLC-γ1, P65, ERKI/II, and JAK/STATs required for peripheral CD8 T cell persistent function. Our data transcriptomic and protein data uncovered the mechanism of how TCF-7 impacting peripheral CD8 T cell inflammatory cytokine production, CD8 T cell activation, and apoptosis. Our pre-clinical model showed that CD8 T cells from TCF-7 cKO mice did not cause GVHD, but effectively cleared primary tumor cells.