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

• Published in: Nature immunology
• Main Authors: Weiss, Sarah A., Huang, Amy Y., Fung, Megan E., Martinez, Daniela, Chen, Alex C. Y., LaSalle, Thomas J., Miller, Brian C., Scharer, Christopher D., Hegde, Mudra, Nguyen, Thao H., Rowe, Jared H., Osborn, Jossef F., Patterson, Dillon G., Sifnugel, Natalia, Mei-An Nolan, C., Davidson, Richard A., Schwartz, Marc A., Bally, Alexander P. R., Neeld, Dennis K., LaFleur, Martin W., Boss, Jeremy M., Doench, John G., Nicholas Haining, W., Sharpe, Arlene H., Sen, Debattama R.
• Format: Journal Article
• Language: English
• Published: 17.09.2024
• ISSN: 1529-2908; 1529-2916; 1529-2916
• DOI: 10.1038/s41590-024-01961-3

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.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.