HDAC1 controls the generation and maintenance of effector-like CD8+ T cells during chronic viral infection

Rica, R.; Waldherr, M.; Schülein, M.; Miyakoda, E.; Sandner, L.; Stolz, V.; Waltenberger, D.; Krausgruber, T.; Bock, C.; Boucheron, N.; Ellmeier, W.; Sakaguchi, S.

doi:10.1101/2024.02.28.580886

bioRxiv · 10.1101/2024.02.28.580886

HDAC1 controls the generation and maintenance of effector-like CD8+ T cells during chronic viral infection

Rica, R.·Waldherr, M.·Schülein, M.·Miyakoda, E.·Sandner, L.·Stolz, V.·Waltenberger, D.·Krausgruber, T.·Bock, C.·Boucheron, N.·Ellmeier, W.·Sakaguchi, S.

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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. HighlightsO_LIHDAC1 promotes the generation of CX3CR1+ effector-like Tex cell subsets in chronic viral infection in a CD8+ T cell-intrinsic manner. C_LIO_LIDeletion of HDAC1 leads to an increase of a cell subset enriched in exhaustion markers and is accompanied with elevated viremia. C_LIO_LIHDAC1 is required for the maintenance of the CX3CR1+ Tex cell pool. C_LIO_LIHDAC1 deletion alters the chromatin landscape at effector-like signature gene loci in progenitor Tex cells. C_LI

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Rica, R., Waldherr, M., Schülein, M., Miyakoda, E., Sandner, L., Stolz, V., Waltenberger, D., Krausgruber, T., Bock, C., Boucheron, N., Ellmeier, W., Sakaguchi, S.. 2024-03-01. HDAC1 controls the generation and maintenance of effector-like CD8+ T cells during chronic viral infection. https://doi.org/10.1101/2024.02.28.580886

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