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

Authors :
McLane LM
Ngiow SF
Chen Z
Attanasio J
Manne S
Ruthel G
Wu JE
Staupe RP
Xu W
Amaravadi RK
Xu X
Karakousis GC
Mitchell TC
Schuchter LM
Huang AC
Freedman BD
Betts MR
Wherry EJ
Source :
Cell reports [Cell Rep] 2021 May 11; Vol. 35 (6), pp. 109120.
Publication Year :
2021

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 <subscript>EX</subscript> s). T <subscript>EX</subscript> s had a higher ratio of nuclear Eomes:T-bet than memory T cells (T <subscript>MEM</subscript> s) 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 <subscript>MEM</subscript> , whereas low nuclear T-bet in T <subscript>EX</subscript> leads to a dominant effect of Eomes that acts as a weaker repressor of Pdcd1. Blocking PD-1 signaling in T <subscript>EX</subscript> s 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 <subscript>EX</subscript> biology.<br />Competing Interests: Declaration of interests E.J.W. has consulting agreements with and/or is on the scientific advisory board for Merck, Elstar, Janssen, Related Sciences, Synthekine, and Surface Oncology. E.J.W. is a founder of Surface Oncology and Arsenal Biosciences. E.J.W. has a patent licensing agreement on the PD-1 pathway with Roche/Genentech.<br /> (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Details

Language :
English
ISSN :
2211-1247
Volume :
35
Issue :
6
Database :
MEDLINE
Journal :
Cell reports
Publication Type :
Academic Journal
Accession number :
33979613
Full Text :
https://doi.org/10.1016/j.celrep.2021.109120