Human tissue-resident memory T cells are defined by core transcriptional and functional signatures in lymphoid and mucosal sites

Tissue resident memory T cells (TRM) mediate optimal protection to site-specific pathogens in mouse models and are key targets for vaccines. In humans, the existence and defining properties of Positive remain unclear. Here, we performed in-depth transcriptome profiling and phenotypic and functional analyses of circulating and resident memory CD4+ and CD8+T cells from lungs, spleens, blood and intestines of 72 individuals, revealing a core gene set conserved between tissues, species, and T cell lineages. Human Positive exhibit increased expression of specific adhesion and regulatory molecules, increased capacity for pro-inflammatory and regulatory cytokine production, and downregulation of molecules controlling responses to chemokines, tissue egress, and cell cycle control compared with circulating Negative cells. We further identify subsets of genes exhibiting tissue-specific expression patterns for mucosal and lymphoid sites. Our results indicate that human Positive constitute a subset distinct from circulatory Negative, with important implications for promoting anatomic localization of memory responses.