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. We are particularly interested in the role that transcription enhancers play in these processes, as they have been shown to be key determinants of cellular differentiation in many contexts.
Transcriptional enhancers (TEs) can occur many kilobases from the genes that they regulate, and thus, which TE regulates which gene isn’t always clear. We have employed HI-C – a method that allows global mapping of gene-TE interactions - to determine how modulated TE engagement regulates T cell differentiation. Generating high-resolution HI-C maps for each stage of virus-specific T cell differentiation, we find that differentiation of naïve T cells results in large scale loss and gain of pre-existing gene-TE interactions, making naïve and effector T cells quite distinct. However, importantly, many of the changes acquired through effector cell differentiation are maintained in memory T cells, providing a likely explanation for their rapid reactivity following reinfection. Further, we find that disruption of cell-type appropriate gene-TE engagement, studied using a mouse with a mutation in SATB1 – a protein that regulates gene-TE communication – results in an altered transcriptome and altered immunity. Thus, taken together, our data show a critical role for regulated TE usage in mediating T cell differentiation.