SATB1 is a master gatekeeper that limits virus-specific CD8⁺ T cell differentiation

Abstract Special AT-rich sequence binding protein-1 (SATB1) is a chromatin binding protein that has key roles in ensuring appropriate chromatin structure and remodelling during T cell development. While a role for SATB1 in both CD4 +T regulatory and CD4 +T H2 lineage specific function has been described, little is known about its role during virus-specific CD8 +T cell differentiation. Here we demonstrate that SATB1 down regulation is associated with naïve CD8 +T cell activation and subsequent differentiation. Genome wide SATB1 binding indicates that SATB1 is critical for maintaining the naïve CD8 +T cell transcriptional programs prior to activation. Overexpression of SATB1 upon CD8 +T cell activation results in major restraint of virus-specific CD8 +cell differentiation resulting in lower expression of inflammatory chemokine receptors, checkpoint molecules such as PD-1 and limits effector CD8 +T cell infiltration into infected tissues. Moreover, SATB1 over expression maintains high levels of TCF-1 expression and maintenance of the naïve T cell program. Our data suggest that SATB1 expression within naïve CD8 +T cells acts as gatekeeper for maintaining the naïve T cell program, and that down regulation upon activation is required for optimal effector CD8 +T cell differentiation. Supported by grants from the Australian Research Council (DP170102020).