The transcriptional cofactor Tle3 programs resident memory CD8+T cells differentiation [ATAC-seq]

Tissue-resident CD8+ T cells (CD8+ TRM) possess the ability to efficiently eliminate invading pathogens locally and are an essential component of the immune barrier. The upregulation of tissue residency-related genes and the downregulation of tissue egress-related genes are critical for the differentiation and long-term residency of CD8+ TRM. However, the coordinated regulatory mechanisms of these two transcriptional programs remain unclear. Tle3 is a transcriptional cofactor that promotes and maintains the differentiation of circulating memory CD8+ T cell subsets by cooperating with key transcription factors. However, its role in the differentiation of CD8+ TRM remains unknown. Our preliminary studies indicate that Tle3 promotes the differentiation of CD8+ TRM subsets in multiple tissues, including the lung, and serves as a key regulator of TRM differentiation. Transcriptomic analysis suggests that Tle3 regulates CD8+ TRM differentiation by promoting the expression of TRM-associated genes while suppressing tissue egress-related genes, highlighting its crucial role in establishing the transcriptional program of CD8+ TRM and balancing the expression of residency and egress-related genes. Nevertheless, the key downstream molecules regulated by Tle3 and how it coordinates different transcriptional networks remain unclear.