Virus infection triggers the proliferation and differentiation of naïve, quiescent CD8+ (killer) T cells, resulting in a large pool of effector cells now capable of killing infected host cells through the secretion of cytotoxic molecules including granzymes and perforin. Importantly, infection gives rise to a long-lived pool of virus-specific (memory) T cells that reactivate rapidly following re-infection, providing the basis of T cell-mediated immunity. While the different phenotypes and functional capacities of naïve, effector and memory T cells are known to be underscored by unique transcriptomes, how these profiles arise and are maintained is poorly understood. In particular, little is known about how changes in genome organisation reflect or underpin these transcriptional programs.
We utilised Hi-C to map changes in the spatial organisation of long-range genome contacts within naïve, effector and memory virus-specific CD8+ T cells. We observed that the architecture of the naïve CD8+ T cell genome was distinct from that of effector and memory, with extensive changes within discrete functional chromatin domains. However, deletion of the BACH2 or SATB1 transcription factors was sufficient to remodel the naïve chromatin architecture, and engage transcriptional programs characteristic of differentiated cells. These data suggest that the chromatin architecture within naïve CD8+ T cells is preconfigured to undergo autonomous remodelling upon activation, with key transcription factors restraining differentiation by actively enforcing the unique naïve chromatin state.