HDAC1 controls the generation and maintenance of effector-like CD8+ T cells during chronic viral infection
CD8+ T cell exhaustion is a complex process involving the differentiation of persistently activated CD8+ T cells into functionally distinct cell subsets. Here, we investigated the role of the key epigenetic regulator histone deacetylase 1 (HDAC1) in the differentiation of exhausted T (Tex) cells during chronic viral infection. We uncovered that HDAC1 controls the generation and maintenance of effector-like CX3CR1+ Tex cells in a CD8+ T cell-intrinsic manner. Deletion of HDAC1 led to expansion of an alternative Tex subset characterized by high expression of T cell exhaustion markers, and this was accompanied by elevated viremia. HDAC1 bound to and facilitated an open chromatin state of effector-like signature gene loci in progenitor Tex cells, thereby priming cell fate specification toward the CX3CR1+ Tex subset. Our study uncovers a selective role for HDAC1 in CX3CR1+ Tex subset differentiation, which is essential for controlling viral load during chronic infection.
Authors
- Ricardo A. Orbegozo-Medina (ORCID: https://orcid.org/0000-0002-5281-9718)
- Lisa Sandner (ORCID: https://orcid.org/0000-0003-2831-2623)
- Darina Waltenberger
- Shinya Sakaguchi (ORCID: https://orcid.org/0000-0002-0591-2469)
- Davide Seruggia (ORCID: https://orcid.org/0000-0001-5014-0499)
- Wilfried Ellmeier (ORCID: https://orcid.org/0000-0001-8192-8481)
- Monika Waldherr (ORCID: https://orcid.org/0000-0003-1284-0616)
- Thomas Krausgruber (ORCID: https://orcid.org/0000-0002-1374-0329)
- Ana P. Kutschat (ORCID: https://orcid.org/0000-0002-6360-873X)
- Ramona Rîca (ORCID: https://orcid.org/0000-0001-5501-8513)
- Christoph Bock (ORCID: https://orcid.org/0000-0001-6091-3088)
- Nicole Boucheron (ORCID: https://orcid.org/0000-0002-4979-8311)
- Valentina Stolz
- Marlene Schülein (ORCID: https://orcid.org/0009-0007-0468-7064)
- Emi Miyakoda (ORCID: https://orcid.org/0009-0005-5764-9198)
- Jing Zhang (ORCID: https://orcid.org/0000-0002-5132-7076)
Institutions
- Austrian Academy of Sciences (AT)
- Austrian Research Institute for Artificial Intelligence (AT)
- Hochschule Campus Wien (AT)
- Institute of Art (PL)
- CeMM Research Center for Molecular Medicine (AT)
- Institute of Immunology (HR)
- Medical University of Vienna (AT)
Publication Details
- Journal
- The Journal of Experimental Medicine
- Published
- 2025-05-21
- DOI
- https://doi.org/10.1084/jem.20240829
- Citations
- 5
- Primary Topic
- Histone Deacetylase Inhibitors Research
- Type
- article
- Field-Weighted Citation Impact
- 4.03
Funders
- Austrian Science Fund
- China Scholarship Council
- Medizinische Universität Wien
- H2020 Marie Skłodowska-Curie Actions