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Vaccines and Immunoinformatics Approaches · Journal article
The Journal of Immunology · July 28, 2026
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This is a mechanistic immunology study identifying exhausted-like lung tissue-resident memory CD8+ T cells (TRM-ELs) as a distinct population critical for heterologous protection against influenza in mice and humans. The work demonstrates that TRM-ELs, unlike conventional TRMs, depend on local TCR signaling and enhanced degranulation capacity to mediate rapid antiviral recall responses, laying groundwork for mucosal vaccine design.
Mechanistic comparative analysis of human and mouse lung tissue-resident memory CD8+ T cells. Antigen-specific lung tissue-resident memory CD8+ T cells isolated from humans and mice, with focus on influenza-specific populations. Intervention: Analysis of TRM-EL phenotype, transcriptional programs, TCR signaling dependency, and degranulation capacity; experimental impairment of degranulation. Compared with: Conventional TRM (TRM-Con) populations; intact versus impaired TRM-EL degranulation.
PD-1HI CD103LO exhausted-like TRMs (TRM-ELs) identified as distinct from PD-1LO CD103HI conventional TRMs in lung tissue Local TCR signaling is critical for TRM-EL maintenance, unlike TCR-independent conventional TRMs Intact TRM-ELs are indispensable for heterologous protection; conventional TRMs do not exhibit comparable efficiency
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This discovery identifies a novel mechanistic target for universal respiratory mucosal vaccine development. However, translation to clinical efficacy in humans remains unproven and requires validation in human challenge or vaccination trials.
Mechanistic discovery in human and mouse lung tissue identifying a previously unrecognized TRM subset and its role in heterologous protection, but lacks clinical endpoint data or human efficacy demonstration.
As stated by the source record.
This discovery identifies a novel mechanistic target for universal respiratory mucosal vaccine development. However, translation to clinical efficacy in humans remains unproven and requires validation in human challenge or vaccination trials.
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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)
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