Resident memory T cell development is associated with AP-1 transcription factor upregulation across anatomical niches.

Tissue-resident memory T (T ) cells play a central role in immune responses to pathogens across all barrier tissues after infection. However, the underlying mechanisms that drive T 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 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 signature of 60 genes across skin and siIEL that can effectively distinguish T from circulating T cell populations, providing a more specific T signature than what was previously generated by comparing bulk T to naïve or non-tissue resident memory populations. This updated T signature included the AP-1 transcription factor family members and . Moreover, ATACseq analysis detected an enrichment of AP-1-specific motifs at open chromatin sites in mature T . tissue imaging detected nuclear co-localization of AP-1 members and in resting CD8 T >100 days post-infection. Taken together, these results reveal a critical role of AP-1 transcription factor members in T biology and suggests a novel mechanism for rapid reactivation of resting T in tissue upon antigen encounter.