Human γδ T cells in diverse tissues exhibit site-specific maturation dynamics across the life span

During ontogeny, gamma delta T cells emerge from the thymus and directly seed peripheral tissues for in situ immunity. However, their functional role in humans has largely been defined from blood. Here, we analyzed the phenotype, transcriptome, function, and repertoire of human gamma delta T cells in blood and mucosal and lymphoid tissues from 176 donors across the life span, revealing distinct profiles in children compared with adults. In early life, clonally diverse V delta 1 subsets predominate across blood and tissues, comprising na & iuml;ve and differentiated effector and tissue repair functions, whereas cytolytic V delta 2 subsets populate blood, spleen, and lungs. With age, V delta 1 and V delta 2 subsets exhibit clonal expansions and elevated cytolytic signatures, which are disseminated across sites. In adults, V delta 2 cells predominate in blood, whereas V delta 1 cells are enriched across tissues and express residency profiles. Thus, antigenic exposures over childhood drive the functional evolution and tissue compartmentalization of gamma delta T cells, leading to age-dependent roles in immunity.