SATB1 is a key regulator of quiescence in stem-like CD8+ T cells [ATAC-seq]

Chronic infections and cancers induce CD8+ T cell exhaustion, but within this exhausted CD8+ T cell pool, a self-renewing, stem-like subset known as progenitor CD8+ T (TPRO) cells play a crucial role in maintaining long-term immunity. These TPRO cells exhibit stem-like characteristics, including quiescence, multipotency, and self-renewal, which are the cardinal features of memory T cells. However, the mechanisms that preserve their stem-like properties under chronic antigen stimulation remain unclear. In this study, we identified that SATB1 as a shared feature is highly expressed in both TPRO and memory CD8+ T cells. While the role of SATB1 in stem-like CD8+ T cells remains unknown, its function as epigenetic regulator in promoting quiescence in hematopoietic stem cells led us to hypothesize that SATB1 plays a pivotal role in regulating the stemness of TPRO and memory CD8+ T cells. To test this hypothesis, we employed CRISPR-mediated gene editing to delete Satb1 gene specifically in CD8+ T cells. Upon chronic LCMV infection, we found that SATB1-deficient CD8+ T cells failed to maintain TPRO subset with enhanced transition towards terminally differentiated cells. Similarly, the SATB1 deficiency in acute viral infection impaired the formation of memory CD8+ T cells. Mechanistically, our multi-omic assays revealed that SATB1 regulates the chromatin accessibility and transcriptional activities of stemness-associated genes, such asTcf7, Bach2,andMyb. Overall, our results underscore the critical role of SATB1 in maintaining the transcriptional and epigenetic features of stem-like CD8+ T cells, shedding light on the previously unappreciated regulatory mechanisms that sustain the stemness of antigen-specific CD8+ T cells.