Hdac1 as an early determinant of intermediate-exhausted CD8 + T cell fate in chronic viral infection

Wei Hu; Shengen Shawn Hu; Shaoqi Zhu; Weiqun Peng; Vladimir P Badovinac; Chongzhi Zang; Xudong Zhao; Hai-Hui Xue

doi:10.1073/pnas.2502256122

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Hdac1 as an early determinant of intermediate-exhausted CD8 + T cell fate in chronic viral infection

Journal article

Peer reviewed

Hdac1 as an early determinant of intermediate-exhausted CD8 + T cell fate in chronic viral infection

Wei Hu, Shengen Shawn Hu, Shaoqi Zhu, Weiqun Peng, Vladimir P Badovinac, Chongzhi Zang, Xudong Zhao and Hai-Hui Xue

Proceedings of the National Academy of Sciences - PNAS, Vol.122(19), e2502256122

05/13/2025

DOI: 10.1073/pnas.2502256122

PMCID: PMC12088444

PMID: 40333757

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Abstract

The exhausted CD8+ T (TEX) cells consist of distinct subsets including Tcf1+ stem-like, Tcf1–Cx3cr1+ intermediate (TEX-int) and Tcf1–Cx3cr1– terminally exhausted cells; yet, epigenetic determinants of TEX subset differentiation remain incompletely understood. Using chronic viral infection, we show that histone deacetylase 1 (Hdac1) was specifically required for the formation of antigen-specific TEX-int cells at the effector phase of responses. Single-cell transcriptomics validated that Hdac1 deficiency depleted TEX-int cells and revealed that Hdac1 was critical for positive regulation of TEX-int-characteristic genes, including Cx3cr1, Cxcr6, and Klf2. Furthermore, profiling chromatin accessibility landscape in TEX subsets demonstrated that loss of Hdac1 resulted in a prevalent increase in chromatin open state, as evidently observed at the exhaustion program genes, which were linked to induced expression of exhaustion-inducing Tox transcription factor, PD1 and Lag3 coinhibitory receptors in TEX cells. Hdac1 thus has dual regulatory functions: promoting TEX-int cell fate and preventing excessive activation of the exhaustion program to curtail uncontrolled virus replication.

Cell Differentiation

Animals

CD8-Positive T-Lymphocytes - immunology

CD8-Positive T-Lymphocytes - metabolism

CX3C Chemokine Receptor 1 - genetics

CX3C Chemokine Receptor 1 - metabolism

Hepatocyte Nuclear Factor 1-alpha - metabolism

Histone Deacetylase 1 - genetics

Histone Deacetylase 1 - immunology

Histone Deacetylase 1 - metabolism

Kruppel-Like Transcription Factors

Lymphocytic Choriomeningitis - immunology

Lymphocytic choriomeningitis virus - immunology

Mice

Mice, Inbred C57BL

Persistent Infection - immunology

Details

Title: Subtitle: Hdac1 as an early determinant of intermediate-exhausted CD8 + T cell fate in chronic viral infection
Creators: Wei Hu - Hackensack University Medical Center
Shengen Shawn Hu - University of Virginia Cancer Center
Shaoqi Zhu - Sun Yat-sen University
Weiqun Peng - George Washington University
Vladimir P Badovinac - Department of Pathology, University of Iowa, Iowa City, IA 52242
Chongzhi Zang - University of Virginia Cancer Center
Xudong Zhao - Department of Otolaryngology Head and Neck Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, China
Hai-Hui Xue - Division of Research and Development, New Jersey Veterans Affairs Health Care System, East Orange, NJ 07018
Resource Type: Journal article
Publication Details: Proceedings of the National Academy of Sciences - PNAS, Vol.122(19), e2502256122
DOI: 10.1073/pnas.2502256122
PMID: 40333757
PMCID: PMC12088444
NLM abbreviation: Proc Natl Acad Sci U S A
ISSN: 1091-6490
eISSN: 1091-6490
Publisher: NATL ACAD SCIENCES
Grant note: BX005771 / U.S. Department of Veterans Affairs (VA) 2022YFE 0131800 / MOST | National Key Research and Development Program of China (NKPs) CA290808 / HHS | NIH | National Cancer Institute (NCI) AI114543 / HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID) AI121080 / HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID) AI112579 / HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID)
Language: English
Date published: 05/13/2025
Academic Unit: Pathology
Record Identifier: 9984821345002771

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