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NIH grant 1R01AI203641-01: Molecular mechanisms of protective lung resident memory T cells
Institute: {'code': 'AI', 'abbreviation': 'NIAID', 'name': 'National Institute of Allergy and Infectious Diseases', 'admin_org_id': '12500003', 'admin_funding_url': ''}. PI: Chaofan Li. Award: $713396.
Start: 2026-08-21T00:00:00.
Abstract
The unique single-layer structure of the lung makes it exhibit an antiviral immune response that
differs from other barrier tissues. Respiratory viral infections, particularly 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. Thus, there is an unmet
need to comprehensively study the lung TRM-mediated broad-spectrum protection for
developing strategies to prevent influenza infection. Our preliminary studies have identified a
unique respiratory TRM population in humans and mice: PD-1HI CD103LO exhausted-like TRMs
(TRM-ELs), which differ from PD-1LO CD103HI conventional TRMs (TRM-Cons) observed in
most barrier tissues. Lung PD-1HI TRM-ELs exhibited unique transcriptional and signaling
programs distinct from CD103HI TRM-Cons. Importantly, the intact TRM-EL is indispensable for
heterologous protection, while TRM-Cons are not. This proposal aims to define the
transcriptional and epigenetic mechanisms maintaining the protective TRM-ELs, dissect the
molecular pathways driving the robust and fast protective responses of TRM-ELs during
influenza reinfection, and evaluate the immunization strategies to establish durable TRM-EL-
mediated broad-spectrum protection, including against highly pathogenic avian influenza
A(H5N1). Using unique genetic mouse models, cutting-edge multi-omics assays, and innovative
mucosal vaccination strategies, we will identify the regulatory networks and key protective
factors that endow lung TRM-ELs with their long-lasting superior protection against homologous
and heterologous influenza infection. These results will lay the foundation for the development
of universal respiratory mucosal vaccines to induce sustained locl immunity against influenza
infection.document fetched 2026-08-30 02:46