Role of nuclear localization in the regulation and function of T-bet and Eomes in exhausted CD8 T cells

Cell Rep. 2021 May 11;35(6):109120. doi: 10.1016/j.celrep.2021.109120.


The transcription factors T-bet and Eomesodermin (Eomes) regulate CD8 T cell exhaustion through undefined mechanisms. Here, we show that the subcellular localization of T-bet and Eomes dictate their regulatory activity in exhausted T cells (TEXs). TEXs had a higher ratio of nuclear Eomes:T-bet than memory T cells (TMEMs) during chronic lymphocytic choriomeningitis virus (LCMV) infection in preclinical cancer models and in human tumors. Biochemically, T-bet and Eomes compete for the same DNA sequences, including the Pdcd1 T-box. High nuclear T-bet strongly represses Pdcd1 transcription in TMEM, whereas low nuclear T-bet in TEX leads to a dominant effect of Eomes that acts as a weaker repressor of Pdcd1. Blocking PD-1 signaling in TEXs increases nuclear T-bet, restoring stronger repression of Pdcd1, and driving T-bet-associated gene expression programs of chemotaxis, homing, and activation. These data identify a mechanism whereby the T-bet-Eomes axis regulates exhaustion through their nuclear localization, providing insights into how these transcription factors regulate TEX biology.

Keywords: Eomes; PD-1; T cell exhaustion; T-bet; cancer; checkpoint blockade; chronic infection; exhausted T cell reinvigoration.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / metabolism*
  • Cell Differentiation
  • Humans
  • Mice
  • Signal Transduction
  • T-Box Domain Proteins / metabolism*


  • Eomes protein, mouse
  • T-Box Domain Proteins