Site-specific development and progressive maturation of human tissue-resident memory T cells over infancy and childhood

Abstract

Infancy and childhood are critical life stages for generating immune memory to protect against pathogens; however, the timing, location, and pathways for memory development in humans remain elusive. Here, we investigated Tcells in mucosal sites, lymphoid tissues, and blood from 96 pediatric donors aged 0-10 years using phenotypic, functional, and transcriptomic profiling. Our results revealed that memory Tcells preferentially localized in the intestines and lungs during infancy and accumulated more rapidly in mucosal sites compared with blood and lymphoid organs, consistent with site-specific antigen exposure. Early life mucosal memory Tcells exhibit distinct functional capacities and stem-like transcriptional profiles. In later childhood, they progressively adopt proinflammatory functions and tissue-resident signatures, coincident with increased Tcell receptor (TCR) clonal expansion in mucosal and lymphoid sites. Together, our findings identify staged development of memory Tcells targeted to tissues during the formative years, informing how we might promote and monitor immunity in children.