Armed and Ready: Transcriptional Regulation of Tissue-Resident Memory CD8 T Cells

A fundamental benefit of immunological memory is the ability to respond in an enhanced manner upon secondary encounter with the same pathogen. Tissue-resident memory CD8 T (T-RM) cells contribute to improved protection against reinfection through the generation of immediate effector responses at the site of pathogen entry. Key to the potential of T-RM cells to develop rapid recall responses is their location within the epithelia of the skin, lungs, and intestines at prime entry sites of pathogens. T-RM cells are among the first immune cells to respond to pathogens that have been previously encountered in an antigen-specific manner. Upon recognition of invading pathogens, T-RM cells release IFN-gamma and other pro-inflammatory cytokines and chemokines. These effector molecules activate the surrounding epithelial tissue and recruit other immune cells including natural killer (NK) cells, B cells, and circulating memory CD8 T cells to the site of infection. The repertoire of T-RM effector functions also includes the direct lysis of infected cells through the release of cytotoxic molecules such as perforin and granzymes. The mechanisms enabling T-RM cells to respond in such a rapid manner are gradually being uncovered. In this review, we will address the signals that instruct T-RM generation and maintenance as well as the underlying transcriptional network that keeps T-RM cells in a deployment-ready modus. Furthermore, we will discuss how T-RM cells respond to reinfection of the tissue and how transcription factors may control immediate and proliferative T-RM responses.