Abstract
Tissue-resident memory T (T (RM) ) cells play a central role in immune responses to pathogens across all barrier tissues after infection. However, the underlying mechanisms that drive T (RM) differentiation and priming for their recall effector function remains unclear. In this study, we leveraged both newly generated and publicly available single-cell RNA-sequencing (scRNAseq) data generated across 10 developmental time points to define features of CD8 T (RM) across both skin and small-intestine intraepithelial lymphocytes (siIEL). We employed linear modeling to capture temporally-associated gene programs that increase their expression levels in T cell subsets transitioning from an effector to a memory T cell state. In addition to capturing tissue-specific gene programs, we defined a consensus T (RM) signature of 60 genes across skin and siIEL that can effectively distinguish T (RM) from circulating T cell populations, providing a more specific T (RM) signature than what was previously generated by comparing bulk T (RM) to naïve or non-tissue resident memory populations. This updated T (RM) signature included the AP-1 transcription factor family members Fos, Fosb and Fosl2 . Moreover, ATACseq analysis detected an enrichment of AP-1-specific motifs at open chromatin sites in mature T (RM) . CyCIF tissue imaging detected nuclear co-localization of AP-1 members Fosb and Junb in resting CD8 T (RM) >100 days post-infection. Taken together, these results reveal a critical role of AP-1 transcription factor members in T (RM) biology and suggests a novel mechanism for rapid reactivation of resting T (RM) in tissue upon antigen encounter.