Specific niches for lung-resident memory CD8+ T cells at the site of tissue regeneration enable CD69-independent maintenance

CD8⁺ tissue-resident memory T cells (T_RM cells) reside permanently in nonlymphoid tissues and provide a first line of protection against invading pathogens. However, the precise localization of CD8⁺ T_RM cells in the lung, which physiologically consists of a markedly scant interstitium compared with other mucosa, remains unclear. In this study, we show that lung CD8⁺ T_RM cells localize predominantly in specific niches created at the site of regeneration after tissue injury, whereas peripheral tissue-circulating CD8⁺ effector memory T cells (T_EM cells) are widely but sparsely distributed in unaffected areas. Although CD69 inhibited sphingosine 1-phosphate receptor 1-mediated egress of CD8⁺ T cells immediately after their recruitment into lung tissues, such inhibition was not required for the retention of cells in the T_RM niches. Furthermore, despite rigid segregation of T_EM cells from the T_RM niche, prime-pull strategy with cognate antigen enabled the conversion from T_EM cells to T_RM cells by creating de novo T_RM niches. Such damage site-specific localization of CD8⁺ T_RM cells may be important for efficient protection against secondary infections by respiratory pathogens.