To settle or wander Transcriptional regulation and recall responses of tissue-resident memory T cells

Tissue-resident memory CD8⁺T (T_RM) cells localize to barrier tissues, where they mediate efficient local protection against reinvading pathogens. T_RM cells are thus crucial for tissue immunity, but many aspects of T_RM cell biology, including the transcription factors regulating T_RM development and their fate following reinfection, have remained incompletely understood. In this thesis, we have studied the transcriptional program governing tissue residency and the secondary responses of T_RM cells. Our research highlights the transcription factors Hobit and Blimp-1 as central drivers of T_RM formation through the suppression of tissue-egress pathways. Hobit is expressed by T_RM cells throughout tissues and identifies early commitment to the T_RM lineage. Hobit and Blimp-1 further contribute to T_RM cell identity by controlling the maintenance of cytotoxic effector functions. In contrast, the transcription factor Eomes regulates T_RM cell differentiation by restricting the formation of T_RM precursors and favoring T_CM development. Following reinfection, pathogen-specific T_RM cells contribute substantially to local and systemic CD8⁺ T cell responses, and give rise to a functionally distinct subset of secondary circulating memory CD8⁺ T cells. However, following inflammation in the absence of antigen, the maintenance of non-specific T_RM populations is regulated by local tissue damage. Circulating memory CD8⁺ T cells only minimally contribute to secondary effector and memory responses at mucosal sites after reinfection. Taken together, our findings provide important insights into the mechanisms controlling the formation, maintenance, and secondary responses of T_RM cells, which may be exploited to harness the superior protective capacity of T_RM cells for future therapeutic approaches.