CTCF facilitates subset-specific chromatin interactions to limit the formation of memory CD8+ T cells [HiC]

CD8+ T cells provide protection from infection and tumor growth, and many current immunotherapies target molecules that enhance CD8+ T cell function and differentiation. The transcriptional programs orchestrating CD8+ T cell differentiation in response to infection has been described, but the changes in spatial chromatin organization accompanying effector and memory CD8+ T cell differentiation is unknown, despite research showing the importance of long-range chromatin interactions for transcriptional regulation in various cell types. Here, we studied how genome organization is integrated with CD8+ T cell differentiation and investigated the role of CTCF, a key factor that regulates genome organization through blocking or facilitating chromatin interactions, in regulating CD8+ T cell fates. We observed T cell subset-specific changes in chromatin organization and CTCF binding, and revealed weak-affinity CTCF binding is needed to promote terminal differentiation of CD8+ T cells by coordinating chromatin interactions that regulate transcriptional programs driving CD8+ T cell differentiation. Overall design: Sorted OT-I cells day 0 or 7 days post infection with Lm-OVA