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Epigenetic tuning of PD-1 expression improves exhausted T cell function and viral control.

Sarah A WeissAmy Y HuangMegan E FungDaniela MartinezAlex C Y ChenThomas J LaSalleBrian C MillerChristopher D ScharerMudra HegdeThao H NguyenJared H RoweJossef F OsbornDillon G PattersonNatalia SifnugelC Mei-An NolanRichard A DavidsonMarc Andre SchwartzAlexander P R BallyDennis K NeeldMartin W LaFleurJeremy M BossJohn G DoenchW Nicholas HainingArlene H SharpeDebattama R Sen
Published in: Nature immunology (2024)
PD-1 is a key negative regulator of CD8 + T cell activation and is highly expressed by exhausted T cells in cancer and chronic viral infection. Although PD-1 blockade can improve viral and tumor control, physiological PD-1 expression prevents immunopathology and improves memory formation. The mechanisms driving high PD-1 expression in exhaustion are not well understood and could be critical to disentangling its beneficial and detrimental effects. Here, we functionally interrogated the epigenetic regulation of PD-1 using a mouse model with deletion of an exhaustion-specific PD-1 enhancer. Enhancer deletion exclusively alters PD-1 expression in CD8 + T cells in chronic infection, creating a 'sweet spot' of intermediate expression where T cell function is optimized compared to wild-type and Pdcd1-knockout cells. This permits improved control of chronic infection without additional immunopathology. Together, these results demonstrate that tuning PD-1 via epigenetic editing can reduce CD8 + T cell dysfunction while avoiding excess immunopathology.
Keyphrases
  • poor prognosis
  • binding protein
  • mouse model
  • dna methylation
  • crispr cas
  • sars cov
  • oxidative stress
  • wild type
  • induced apoptosis
  • young adults
  • working memory
  • endoplasmic reticulum stress