TCR signaling dynamically regulates TCF1 expression and effector differentiation

Abstract T Cell Factor 1, or TCF1, is a transcription factor required for thymic T cell development, memory T cell formation, and maintenance of exhausted/dysfunctional T cell stem/progenitors in tumors and chronic infection. However, TCF1 regulation and function during T cell activation is not well-understood. We analyzed the expression kinetics of Tcf7 mRNA, encoding TCF1 (RNA-SEQ) and TCF1 protein (flow cytometry and western immunoblotting) in CD8 T cells during the initial hours and cell divisions following activation in vivo. Naive CD8 T cells robustly express TCF1. Within 6 hours after activation in L. monocytogenes-infected B6 mice, antigen-specific CD8 T cells downregulated Tcf7 mRNA/TCF1 protein, only to re-express both prior to undergoing the first cell division. We observed a similar pattern of TCF1 kinetics in polyclonal CD8 and CD4 T cells activated with anti-CD3/CD28 antibody and PMA/ionomycin, which activates signaling pathways downstream of the T cell receptor (TCR). We further determined that the magnitude of pre-division TCF1 downregulation correlated with cognate peptide concentration and TCR avidity, but also with higher granzyme B expression during later cell divisions. Thus, our data suggests that the pre-division TCF1 drop is regulated by TCR signaling strength and may determine effector fate. By decoding TCF1 regulation during T cell activation, we could gain insights allowing us to target TCF1 to augment or inhibit effector T cell function in different disease contexts, including cancer, chronic infection, and autoimmunity. Supported by grants from NHI (T32 GM137793-02, R37 CA263614)