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

Chen, Z., Ji, Z., Ngiow, S. F., Manne, S., Cai, Z., Huang, A. C., Johnson, J., Staupe, R. P., Bengsch, B., Xu, C., Yu, S., Kurachi, M., Herati, R. S., Vella, L. A., Baxter, A. E., Wu, J. E., Khan, O., Beltra, J. C., Giles, J. R., Stelekati, E., McLane, L. M., Lau, C. W., Yang, X., Berger, S. L., Vahedi, G., Ji, H., Wherry, E. J.



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.