Tcf1 and Lef1 transcription factors establish CD8⁺ T cell identity through intrinsic HDAC activity

The CD4⁺ and CD8⁺ T cell dichotomy is essential for effective cellular immunity. How individual T cell identity is established remains poorly understood. Here we show that the high-mobility group (HMG) transcription factors Tcf1 and Lef1 are essential for repressing CD4⁺ lineage-associated genes including Cd4, Foxp3 and Rorc in CD8⁺ T cells. Tcf1- and Lef1-deficient CD8⁺ T cells exhibit histone hyperacetylation, which can be ascribed to intrinsic histone deacetylase (HDAC) activity in Tcf1 and Lef1. Mutation of five conserved amino acids in the Tcf1 HDAC domain diminishes HDAC activity and the ability to suppress CD4⁺ lineage genes in CD8⁺ T cells. These findings reveal that sequence-specific transcription factors can utilize intrinsic HDAC activity to guard cell identity by repressing lineage-inappropriate genes.