TCR signaling dynamically regulates TCF1 expression and effector differentiation

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