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Antigen-mediated NF-κB signaling: key to establishing lung resident T cell memory during influenza infection 2843

Year: 2025
Type: article
Abstract: Description Tissue-resident memory (TRM) CD8 T cells are essential for protective immunity against respiratory pathogens but are also linked to lung pathology and chronic respiratory diseases. Despite their importance, the molecular and biochemical mechanisms governing lung TRM dynamics are not fully understood, notably the regulation of pathogen-specific TRM populations. The establishment of CD8 TRM depends on environmental cues, including antigen exposure, costimulatory signals, and pro-inflammatory cytokines, all of which activate NFκB signaling in CD8 T cells. Our studies demonstrate that chronic TNF signaling adversely affects the development of influenza-specific CD8 TRM via NFκB signaling by impairing TGFβ signaling and altering the expression of key TRM regulators such as CD103, Runx3, and Eomes. Employing novel TetON inducible NFκB models, we found that inhibiting NFκB signaling significantly boosts influenza-specific lung CD8 TRM generation, and that TNF blockade late during influenza infection similarly increases CD8 TRM levels. Ongoing research focuses on how antigen controls CD8 TRM levels. Using a mouse model with impaired TCR-dependent NFκB signaling, we discovered that antigen-dependent NFκB signaling is critical for regulating the levels of influenza-specific CD8 TRM in the lung. Given that respiratory infections are a leading cause of morbidity and mortality, insights from this research could guide the development of improved vaccines and TRM-based immunotherapies. Funding Sources NIH R01 AI110420-01A1 and R56 AI110420-06A1; 1U01CA244314 as well as internal funding from the School of Medicine; NCI CA244314; NIH IB026560; NIH-REACH; T32 GM135744 Topic Categories Lymphocyte Differentiation and Peripheral Maintenance (LYM)
DOI: 10.1093/jimmun/vkaf283.717
Language: English
Subfield: Immunology
Open Access status: bronze
OpenAlex ID: W4416449091
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