T Cell Exhaustion: An Epigenetically Imprinted Phenotypic and Functional Makeover

A recent article in Cell demonstrates that the absence of a single DNA methyltransferase, Dnmt3a, prevents cytotoxic T cells from acquiring the hypofunctional or exhausted phenotype typically seen in chronic viral infections and tumors. Upon establishing a causal relationship between exhaustion-associated epigenetic changes and reduced CD8⁺ T cell function, the authors provided mechanistic evidence that exhaustion constitutes a specific differentiation program.