A critical role for Dnmt1 and DNA methylation in T cell development, function, and survival

The role of DNA methylation and of the maintenance DNA methyltransferase Dn mt1 in the epigenetic regulation of developmental stage- and cell lineage-s pecific gene expression in vivo is uncertain. This is addressed here throug h the generation of mice in which Dnmt1 was inactivated by Cre/loxP-mediate d deletion at sequential stages of T cell development. Deletion of Dnmt1 in early double-negative thymocytes led to impaired survival of TCR alpha bet a (+) cells and the generation of atypical CD8(+)TCR gamma delta (+) cells. Deletion of Dnmt1 in double-positive thymocytes impaired activation-induce d proliferation but differentially enhanced cytokine mRNA expression by nai ve peripheral T cells. We conclude that Dnmt1 and DNA methylation are requi red for the proper expression of certain genes that define fate and determi ne function in T cells.