DNA methylation by DNA methyltransferase 1 is critical for effector CD8 T cell expansion

Transcriptional silencing mediated by DNA methylation is a critical component of epigenetic regulation during early embryonic development in animals. However, the requirement for DNA methylation during activation and differentiation of mature CD8(+) T cells into effector and memory cells is not clear. Using cre-mediated deletion of DNA methyltransferase 1 (Dnmt1)at the time of CD8(+) T cell activation, we investigated the obligation for maintaining patterns of DNA methylation during the generation of Ag-specific effector and memory CD8(+) T cells in response to acute viral infection of mice with lymphocytic choriomeningitis virus. Dnmt1(-/-) CD8(+) T cells failed to undergo the massive CD8(+) T cell expansion characteristic of lymphocytic choriomeningitis virus infection, leading to > 80% reductions in Ag-specific effector CD8(+) T cells at the height of the response. Despite this, Dnmt1(-/-)CD8(+) T cells efficiently controlled the viral infection. Interestingly, the number of Ag-specific Dnmt1(-/-) memory CD8(+) T cells was moderately reduced compared with the reductions seen at day 8 postinfection. Our data suggest that ablation of Dnmt1 and subsequent DNA methylation affect the finite proliferative potential of Ag-specific CD8(+) T cells with moderate effects on their differentiation to effector and memory CD8(+) T cells.