TCF-1-Centered Transcriptional Network Drives an Effector versus Exhausted CD8 T Cell-Fate Decision

TCF-1 is a key transcription factor in progenitor exhausted CD8 T cells (Tex). Moreover, this Tex cell subset mediates responses to PD-1 checkpoint pathway blockade. However, the role of the transcription factor TCF-1 in early fate decisions and initial generation of Tex cells is unclear. Single-cell RNA sequencing (scRNA-seq) and lineage tracing identified a TCF-1⁺Ly108⁺PD-1⁺ CD8 T cell population that seeds development of mature Tex cells early during chronic infection. TCF-1 mediated the bifurcation between divergent fates, repressing development of terminal KLRG1^Hi effectors while fostering KLRG1^Lo Tex precursor cells, and PD-1 stabilized this TCF-1⁺ Tex precursor cell pool. TCF-1 mediated a T-bet-to-Eomes transcription factor transition in Tex precursors by promoting Eomes expression and drove c-Myb expression that controlled Bcl-2 and survival. These data define a role for TCF-1 in early-fate-bifurcation-driving Tex precursor cells and also identify PD-1 as a protector of this early TCF-1 subset. The initiation of the T cell exhaustion program remains poorly understood. In this study, Chen et al. define an effector (Teff) versus exhausted (Tex) CD8 T cell binary-fate decision during chronic infection and find that TCF-1 supports the Tex precursor development by antagonizing Teff-like cell differentiation through multiple transcription factors.