Thesis Felix Behr

Summary

Tissue-resident memory CD8+ T (TRM) cells localize to barrier tissues, where they mediate efficient local protection against reinvading pathogens. TRM cells are thus crucial for tissue immunity, but many aspects of TRM cell biology, including the transcription factors regulating TRM 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 TRM cells. Our research highlights the transcription factors Hobit and Blimp-1 as central drivers of TRM formation through the suppression of tissue-egress pathways. Hobit is expressed by TRM cells throughout tissues and identifies early commitment to the TRM lineage. Hobit and Blimp-1 further contribute to TRM cell identity by controlling the maintenance of cytotoxic effector functions. In contrast, the transcription factor Eomes regulates TRM cell differentiation by restricting the formation of TRM precursors and favoring TCM development. Following reinfection, pathogen-specific TRM 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 TRM 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 TRM cells, which may be exploited to harness the superior protective capacity of TRM cells for future therapeutic approaches.