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

Abstract

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+ Tcells. We observe that the architecture of the naive CD8+ Tcell 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+ Tcells results in a chromatin architecture more reminiscent of effector/memory states. This suggests that key transcription factors within naive CD8+ Tcells act to restrain Tcell differentiation by actively enforcing a unique naive chromatin state.