Generation and persistence of human tissue-resident memory T cells in lung transplantation

Tissue-resident memory T cells (T_RM) maintain immunity in diverse sites as determined in mouse models, whereas their establishment and role in human tissues have been difficult to assess. Here, we investigated human lung T_RM generation, maintenance, and function in airway samples obtained longitudinally from human leukocyte antigen (HLA)-disparate lung transplant recipients, where donor and recipient T cells could be localized and tracked over time. Donor T cells persist specifically in the lungs (and not blood) of transplant recipients and express high levels of T_RM signature markers including CD69, CD103, and CD49a, whereas lung-infiltrating recipient T cells gradually acquire T_RM phenotypes over months in vivo. Single-cell transcriptome profiling of airway T cells reveals that donor T cells comprise two T_RM-like subsets with varying levels of expression of T_RM-associated genes, whereas recipient T cells comprised non-T_RM and similar T_RM-like subpopulations, suggesting de novo T_RM generation. Transplant recipients exhibiting higher frequencies of persisting donor T_RM experienced fewer adverse clinical events such as primary graft dysfunction and acute cellular rejection compared with recipients with low donor T_RM persistence, suggesting that monitoring T_RM dynamics could be clinically informative. Together, our results provide spatial and temporal insights into how human T_RM develop, function, persist, and affect tissue integrity within the complexities of lung transplantation.