Active maintenance of CD8⁺ T cell naivety through regulation of global genome architecture

The differentiation of naive CD8⁺ T lymphocytes into cytotoxic effector and memory CTL results in large-scale changes in transcriptional and phenotypic profiles. Little is known about how large-scale changes in genome organization underpin these transcriptional programs. We use Hi-C to map changes in the spatial organization of long-range genome contacts within naive, effector, and memory virus-specific CD8⁺ T cells. We observe that the architecture of the naive CD8⁺ T cell genome is distinct from effector and memory genome configurations, with extensive changes within discrete functional chromatin domains associated with effector/memory differentiation. Deletion of BACH2, or to a lesser extent, reducing SATB1 DNA binding, within naive CD8⁺ T cells results in a chromatin architecture more reminiscent of effector/memory states. This suggests that key transcription factors within naive CD8⁺ T cells act to restrain T cell differentiation by actively enforcing a unique naive chromatin state.