Transcriptional Control of Memory T Cell Differentiation

Tissue-resident memory CD8⁺ T cells (T_RM) are optimally positioned at common sites of pathogen exposure, where they elicit rapid and robust antiviral immune responses. However, the molecular signals controlling tissue residency and homeostasis of T_RM remain unclear. Exploiting a dual-screening platform integrating computational and RNAi in vivo screening approaches, we have identified transcriptional regulators of T_RM differentiation. This strategy revealed numerous transcription factors with indispensable roles in T_RM differentiation and homeostasis. Further, we show that tumor infiltrating lymphocytes (TIL) share a core T_RM transcriptional signature, and that these factors control TIL residency. These results provide novel insight into the biology of T cell residency, which could be leveraged to enhance vaccine efficacy or adoptive therapy treatments against cancer.