HDAC1 controls the generation and maintenance of effector-like CD8<sup>+</sup>T cells during chronic viral infection
Abstract CD8+T cell exhaustion is a complex process that involves 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 cell subset characterized by high expression of T cell exhaustion markers, and this was accompanied by elevated viremia. HDAC1 knockout altered the chromatin landscape in progenitor Tex cells, abrogated the expression of effector-like signature genes and interfered with cell fate specification toward the CX3CR1+Tex cell subset. We conclude that HDAC1 is functionally required for controlling viral load during chronic infection by ensuring adequate CX3CR1+Tex cell subset differentiation.Highlights <jats:list list-type="bullet">HDAC1 promotes the generation of CX3CR1+effector-like Tex cell subsets in chronic viral infection in a CD8+T cell-intrinsic manner.Deletion of HDAC1 leads to an increase of a cell subset enriched in exhaustion markers and is accompanied with elevated viremia.HDAC1 is required for the maintenance of the CX3CR1+Tex cell pool.HDAC1 deletion alters the chromatin landscape at effector-like signature gene loci in progenitor Tex cells..
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Preprint| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
bioRxiv.org - (2024) vom: 04. März Zur Gesamtaufnahme - year:2024 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Rica, Ramona [VerfasserIn] |
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| Links: |
Volltext [kostenfrei] |
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| doi: |
10.1101/2024.02.28.580886 |
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| PPN (Katalog-ID): |
XBI042684072 |
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| 520 | |a Abstract CD8+T cell exhaustion is a complex process that involves 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 cell subset characterized by high expression of T cell exhaustion markers, and this was accompanied by elevated viremia. HDAC1 knockout altered the chromatin landscape in progenitor Tex cells, abrogated the expression of effector-like signature genes and interfered with cell fate specification toward the CX3CR1+Tex cell subset. We conclude that HDAC1 is functionally required for controlling viral load during chronic infection by ensuring adequate CX3CR1+Tex cell subset differentiation.Highlights <jats:list list-type="bullet">HDAC1 promotes the generation of CX3CR1+effector-like Tex cell subsets in chronic viral infection in a CD8+T cell-intrinsic manner.Deletion of HDAC1 leads to an increase of a cell subset enriched in exhaustion markers and is accompanied with elevated viremia.HDAC1 is required for the maintenance of the CX3CR1+Tex cell pool.HDAC1 deletion alters the chromatin landscape at effector-like signature gene loci in progenitor Tex cells. | ||
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| 700 | 1 | |a Schülein, Marlene |4 aut | |
| 700 | 1 | |a Miyakoda, Emi |4 aut | |
| 700 | 1 | |a Sandner, Lisa |4 aut | |
| 700 | 1 | |a Stolz, Valentina |4 aut | |
| 700 | 1 | |a Waltenberger, Darina |4 aut | |
| 700 | 1 | |a Krausgruber, Thomas |4 aut | |
| 700 | 1 | |a Bock, Christoph |4 aut | |
| 700 | 1 | |a Boucheron, Nicole |4 aut | |
| 700 | 1 | |a Ellmeier, Wilfried |4 aut | |
| 700 | 1 | |a Sakaguchi, Shinya |4 aut | |
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