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

Laura M McLane; Shin Foong Ngiow; Zeyu Chen; John Attanasio; Sasikanth Manne; Gordon Ruthel; Jennifer E Wu; Ryan P Staupe; Wei Xu; Ravi K Amaravadi; Xiaowei Xu; Giorgos C Karakousis; Tara C Mitchell; Lynn M Schuchter; Alexander C Huang; Bruce D Freedman; Michael R Betts; E John Wherry

doi:10.1016/j.celrep.2021.109120

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.

Authors

Laura M McLane¹, Shin Foong Ngiow², Zeyu Chen², John Attanasio¹, Sasikanth Manne¹, Gordon Ruthel³, Jennifer E Wu², Ryan P Staupe¹, Wei Xu⁴, Ravi K Amaravadi⁵, Xiaowei Xu⁶, Giorgos C Karakousis⁷, Tara C Mitchell⁵, Lynn M Schuchter⁵, Alexander C Huang⁸, Bruce D Freedman⁹, Michael R Betts¹, E John Wherry¹⁰

Affiliations

¹ Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
² Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Parker Institute for Cancer Immunotherapy, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
³ Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104, USA.
⁴ Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁵ Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁶ Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁷ Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁸ Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Parker Institute for Cancer Immunotherapy, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁹ Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104, USA.
¹⁰ Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Parker Institute for Cancer Immunotherapy, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: wherry@pennmedicine.upenn.edu.

Abstract

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 (T_EXs). T_EXs had a higher ratio of nuclear Eomes:T-bet than memory T cells (T_MEMs) 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 T_MEM, whereas low nuclear T-bet in T_EX leads to a dominant effect of Eomes that acts as a weaker repressor of Pdcd1. Blocking PD-1 signaling in T_EXs 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 T_EX 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*

Substances

Eomes protein, mouse
T-Box Domain Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding