Transcriptional regulator SATB1 limits CD8⁺ T cell population expansion and effector differentiation in chronic...

CD8⁺ T cells are major mediators of antiviral and antitumor immunity. During persistent antigen stimulation as in chronic infection and cancer, however, they differentiate into exhausted T cells that display impaired functionality. Precursors of exhausted T (T_PEX) cells exhibit stem-like properties, including high proliferative, self-renewal and developmental potential, and are responsible for long-term CD8⁺ T cell responses against persistent antigens. Here we identify the chromatin organizer and transcriptional regulator SATB1 as a major regulator of exhausted CD8⁺ T cell differentiation. SATB1 was specifically expressed in T_PEX cells where it limited population expansion and effector differentiation while preserving functionality of CD8⁺ T cells. SATB1 downregulation was required for T_PEX cell-to-effector cell differentiation in chronic infection and contributed to coordinated effector and memory differentiation in acute viral infection. DNA binding of SATB1 regulated gene expression both dependent and independent of chromatin accessibility. Finally, SATB1 limited antitumor CD8⁺ and chimeric antigen receptor T cell immunity. Overall, our results identify SATB1 as a central regulator of precursor fate and effector differentiation of CD8⁺ T cells both in infection and in cancer.