Human lungs maintain tissue-resident memory T cells against a broad spectrum of pathogens.

Immune responses in the lungs are essential for the prevention and control of a wide range of infections. Tissue-resident memory T (TRM) cells are critical for frontline immunity, yet in murine lungs they undergo rapid attrition, raising questions about their durability in the human lung. Here, using a T-cell receptor (TCR)-guided approach integrating single-cell transcriptomics with paired TCR repertoire profiling, we mapped over 87,000 pathogen-specific T cells from human lung tissue across 40 donors, many of whom harbored substantial TRM populations specific to multiple respiratory viruses. These findings suggest, contrary to observations in murine infection models, that the human lung is likely to serve as a reservoir of clonally expanded TRM cells specific to a broad spectrum of pathogens. Although the lung-associated lymph nodes (LLN) contained a small population of TRM cells, most TCRs from highly expanded TRM clones in the lungs were absent in the LLN, suggesting that LLNs are unlikely to serve as a major reservoir for lung TRM cells. While acquisition of the TRM phenotype in the lung was not biased towards specific pathogens, pathogen specificity influenced the transcriptional profiles of CD8+ TRM cells. Notably, influenza A virus (IAV)-specific CD8+ TRM cells expressed significantly higher levels of transcripts linked to tissue residence and effector properties compared to TRM cells specific to other pathogens. Overall, our findings reveal that the human lung retains a stable, yet diverse compartment of pathogen-specific TRM cells, with implications for understanding tissue-resident memory responses that persist after infections and vaccinations.