Axes of heterogeneity in human tissue-resident memory T cells

Tissue-resident memory T cells (TRM) represent a dedicated layer of localized immune memory in virtually every organ throughout the human body. By virtue of their long-term residence in disparate tissues, TRM are shaped by a myriad of site-specific influences and exhibit remarkable heterogeneity in form and function. Here, we review the major axes by which TRM vary, including their surface phenotypes, transcriptional programming, and the tissue-specific adaptations that accrue over their tenancy. We discuss how localization within distinct anatomic niches both within and across major organ systems shapes TRM identity and examine mechanisms and prevailing models for TRM generation. Understanding the drivers of differentiation, function and maintenance of the various subpopulations that together define the TRM lineage may hold the key to unlocking the full potential of TRM to promote localized and protective tissue immunity throughout the body.