PRC2 Mediated Repression in CD8 T cell Exhaustion

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Degree type
Doctor of Philosophy (PhD)
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Genomics and Computational Biology
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Biology
Immunology and Infectious Disease
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2024
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Samareh, Parisa, Florence
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Abstract

CD8 T cells of the immune system are responsible for killing disease-associated cells. Disease settings with periods of prolonged antigen stimulation, such as cancer or chronic infection, result in exhausted CD8 T cells with reduced ability to clear disease. Given that CD8 T cell exhaustion is a cell state, the epigenetic regulation of the dysfunctional phenotype of exhausted CD8 T cells is a promising avenue for therapies aimed at reversing or preventing CD8 T cell exhaustion. Here, utilizing in vitro and in vivo mouse models of CD8 T cell exhaustion, we discover acquisition of a globally repressive chromatin state in CD8 T cell exhaustion compared to naïve and memory CD8 T cells. We show global increase of the repressive histone modification Lysine-27 trimethylation (H3K27me3) in CD8 T cell exhaustion in vitro and in vivo. In accordance with this finding, we observe increased gene expression of the subunit proteins that comprise PRC2, the complex responsible for H3K27me3 deposition, in vivo, in vitro and in human CD8 T cell exhaustion. We investigated H3K27me3 localization in CD8 T cell exhaustion in vitro and found that the repressive mark correlated with lowered gene expression and associated with genes encoding key naïve and memory CD8 T cell proteins necessary for proper CD8 T cell response to antigen re-exposure. Furthermore, inhibition of PRC2 in vitro, through the EED subunit, reduced features of CD8 T cell exhaustion and increased a memory and naïve CD8 T cell gene expression program. To understand the upstream mechanism responsible for the increase in PRC2 in CD8 T cell exhaustion, we identified potential enhancers and cognate transcription factors that may coordinately promote expression of the PRC2 subunits. While gene activation and TF mediated gene expression programs in CD8 T cell exhaustion are well studied, the repression of alternative cell fates in exhaustion is unknown. Our study highlights the importance of the repressive epigenetic landscape in exhausted CD8 T cells and reveals a novel role for PRC2 in CD8 T cell biology.

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Berger, Shelley, L.
Date of degree
2024
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