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Epigenetic tuning of PD-1 expression improves exhausted T cell function and viral control
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Epigenetic tuning of PD-1 expression improves exhausted T cell function and viral control
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Journal Article
Epigenetic tuning of PD-1 expression improves exhausted T cell function and viral control
2024
Overview
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 critical modulator of CD8
+
T cell activation and exhaustion. Sen and colleagues show that a cell-state-specific enhancer tunes PD-1 expression exclusively in exhaustion and that deletion of this enhancer improves CD8
+
T cell function.
Publisher
Nature Publishing Group US,Nature Publishing Group
Subject
/ Animals
/ Biomedical and Life Sciences
/ CD8-Positive T-Lymphocytes - immunology
/ Enhancer Elements, Genetic - genetics
/ Lymphocyte Activation - immunology
/ Lymphocytic Choriomeningitis - immunology
/ Lymphocytic Choriomeningitis - virology
/ Mice
/ Programmed Cell Death 1 Receptor - genetics
