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

• Published in: Cell reports (Cambridge) Vol. 35; no. 6; p. 109120
• Main Authors: McLane, Laura M., Ngiow, Shin Foong, Chen, Zeyu, Attanasio, John, Manne, Sasikanth, Ruthel, Gordon, Wu, Jennifer E., Staupe, Ryan P., Xu, Wei, Amaravadi, Ravi K., Xu, Xiaowei, Karakousis, Giorgos C., Mitchell, Tara C., Schuchter, Lynn M., Huang, Alexander C., Freedman, Bruce D., Betts, Michael R., Wherry, E. John
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 11-05-2021
• Subjects: Animals; cancer; CD8-Positive T-Lymphocytes - metabolism; Cell Differentiation; checkpoint blockade; chronic infection; Eomes; exhausted T cell reinvigoration; Humans; Mice; PD-1; Signal Transduction; T cell exhaustion; T-bet; T-Box Domain Proteins - metabolism; Eomes; checkpoint blockade; chronic infection; exhausted T cell reinvigoration; T cell exhaustion; cancer; PD-1; T-bet
• ISSN: 2211-1247; 2211-1247
• 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.
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•The relative amounts of nuclear T-bet and Eomes T cells partially define exhaustion•PD1 blockade increases nuclear T-bet and upregulates T cell activation and homing genes•T-bet and Eomes recognize and bind to the same T-box domain in the Pdcd1 promoter•Eomes is a weak transcriptional repressor of Pdcd1 in TEXs
McLane et al. demonstrate that T-bet and Eomes expression contributes to exhaustion, but also their nuclear localization, and therefore functional activity, plays a key role. PD-1 blockade restores nuclear T-bet and promotes T cell homing and activation through direct competition with Eomes at gene promoters, such as Pdcd1.