Discovery of Exhausted-like Lung Tissue-Resident Memory T Cells as Key Mediators of Protective Immunity 2257944

Abstract Introduction Respiratory viral infections, especially influenza, remain a major global health challenge, and circulating antibody-based vaccines are limited by frequent surface antigenic drift. In contrast, influenza-specific lung tissue-resident memory CD8+ T cells (TRMs) recognize conserved epitopes and provide both homologous and heterologous protection, serving as a rapid frontline defense during reinfection; however, the mechanisms that sustain and drive their protective functions remain poorly understood. Methods Through analyzing antigen-specific lung TRM from humans and mice, we identified a unique endogenous respiratory TRM population: PD-1HI CD103LO exhausted-like TRMs (TRM-ELs), which differ from PD-1LO CD103HI conventional TRMs (TRM-Cons) observed in most barrier tissues. Results Lung TRM-ELs exhibit unique transcriptional and signaling programs distinct from those of CD103+ TRM-Cons. Unlike previously reported TCR-independent TRM-cons, we demonstrated that local TCR signaling is critical for the maintenance of TRM-ELs. Importantly, the intact TRM-EL is indispensable for heterologous protection, while TRM-Cons don’t exhibit comparable efficiency. Mechanistically, the key molecule mediating TRM degranulation is significantly highly expressed in TRM-ELs, which facilitates the fast recall response and protection against secondary infection. The following experiments reveal that the impaired degranulation of effector molecules in TRM-ELs markedly diminishes the robust protective efficacy and alters the landscape of the anti-viral microenvironment in the lung. Conclusion Taken together, our research provides mechanistic insight into an unrecognized protective lung TRM population and elucidates distinct molecular pathways governing their persistence and antiviral efficacy. These results will lay the foundation for the development of universal respiratory mucosal vaccines to induce sustained local TRM immunity against influenza and related pathogens. Funding Source n/a Topic Categories Mucosal and Regional Immunology (MUC)