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

Abstract

AbstractTissue-resident memory T (TRM) cells play a central role in immune responses to pathogens across all barrier tissues after infection. However, the underlying mechanisms that drive TRMdifferentiation 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 TRMacross 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 TRMsignature of 60 genes across skin and siIEL that can effectively distinguish TRMfrom circulating T cell populations, providing a more specific TRMsignature than what was previously generated by comparing bulk TRMto naïve or non-tissue resident memory populations. This updated TRMsignature included the AP-1 transcription factor family membersFos, FosbandFosl2. Moreover, ATACseq analysis detected an enrichment of AP-1-specific motifs at open chromatin sites in mature TRM.CyCIFtissue imaging detected nuclear co-localization of AP-1 membersFosbandJunbin resting CD8 TRM>100 days post-infection. Taken together, these results reveal a critical role of AP-1 transcription factor members in TRMbiology and suggests a novel mechanism for rapid reactivation of resting TRMin tissue upon antigen encounter.