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

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.