HDAC1 controls the generation and maintenance of effector-like CD8 + T cells during chronic viral infection
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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
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HDAC1 promotes the generation of CX3CR1 + effector-like Tex cell subsets in chronic viral infection in a CD8 + T cell-intrinsic manner.
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Deletion of HDAC1 leads to an increase of a cell subset enriched in exhaustion markers and is accompanied with elevated viremia.
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HDAC1 is required for the maintenance of the CX3CR1 + Tex cell pool.
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HDAC1 deletion alters the chromatin landscape at effector-like signature gene loci in progenitor Tex cells.
