SATB1 maintains naive-like identity in antiviral CD8⁺ T cells by limiting chromatin remodelling at effector gene loci.

Optimal CD8+ T cell differentiation requires the engagement of transcriptional programs that drive effector phenotypes and function, whilst also shutting down transcriptional programs that maintain the naive state. While the distinct factors that underpin each state are well studied, the molecular mechanisms that control the switch from the naive to effector state are not fully understood. Utilising integrated analysis of single-cell genomic data, we identified CD8+ T cell effector transcriptional networks that are restrained in the naive state by the chromatin binding protein Special AT-rich sequence binding protein-1 (SATB1). Utilising a SATB1-Tg model, whereby activated CD8+ T cells are unable to down regulate SATB1 upon activation, we observed limited effector differentiation and an inability to engage effector programs in response to both primary and secondary influenza A virus infection. Mechanistically, SATB1 limited chromatin remodelling at key gene loci required for the full engagement of the CD8+ T cell effector program. Hence, SATB1 is a master gatekeeper that maintains the naive T cell state and whose downregulation is necessary to allow transition from a naive to effector state upon T cell activation. SATB1 modulation may provide new strategies for improving CD8+ T cell longevity and self-renewal capacity in different immunotherapeutic treatments.