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

Zeyu Chen, Zhicheng Ji, Shin Foong Ngiow, Sasikanth Manne, Zhangying Cai, Alexander C. Huang, John Johnson, Ryan P. Staupe, Bertram Bengsch, Caiyue Xu, Sixiang Yu, Makoto Kurachi, Ramin S. Herati, Laura A. Vella, Amy E. Baxter, Jennifer E. Wu, Omar Khan, Jean Christophe Beltra, Josephine R. Giles, Erietta StelekatiLaura M. McLane, Chi Wai Lau, Xiaolu Yang, Shelley L. Berger, Golnaz Vahedi, Hongkai Ji, E. John Wherry

Research output: Contribution to journalArticlepeer-review

Abstract

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 KLRG1Hi effectors while fostering KLRG1Lo 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.

Original languageEnglish (US)
Pages (from-to)840-855.e5
JournalImmunity
Volume51
Issue number5
DOIs
StatePublished - Nov 19 2019

Keywords

  • CD8 T cell exhaustion
  • PD-1
  • cancer
  • chronic infection
  • exhaustion
  • immunotherapy
  • transcriptional circuit

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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