SATB1 is essential in regulating the stemness of antigen-specific CD8+ T cells

In chronic infection and cancer, a subset of self-renewing, antigen-specific CD8+ T cells, termed progenitors, is crucial for long-term immunity and immunotherapy effectiveness.  The mechanisms governing their stemness, however, are not fully understood.  Our single-cell RNA + ATAC sequencing analysis revealed that SATB1 (special AT-rich sequence-binding protein) is exclusively expressed in the progenitor CD8+ T cells during chronic infection. Known for its key role in chromatin organization during T-cell development, SATB1’s unique expression in the progenitor CD8+ T cell led us to hypothesize that it plays a pivotal role in regulating the stemness of the antigen-specific CD8+ T cells. Using the lymphocytic choriomeningitis virus (LCMV) Clone 13 mouse model of chronic infection, the SATB1 gene was deleted in CD8+ T cells via CRISPR/ RNP technology. At day 21 post-infection, the SATB1 deletion resulted in a reduction of virus-specific progenitor CD8+ T cells and a decrease of TCF1 expression. The transcriptomic and epigenomic studies further revealed that SATB1 plays a key role in regulating the chromatin accessibility and transcriptional activities of stemness-associated genes, such as Tcf7, Bach2, and Myb. Overall, our results underscore the critical role of SATB1 in maintaining the transcriptional integrity of progenitor CD8+ T cells in response to antigen activation, which sheds light on the genetic pathways that regulate the stemness of antigen-specific CD8+ T cells.