Trained immunity in the lung
- Department of Pathology, Immunology and Laboratory Medicine, Center for Immunity and Inflammation, Rutgers New Jersey Medical School, United States
Figures
Figure 1
Contrasting trained immunity to adaptive immunity.
Figure generated using BioRender.com.
Tables
Table 1
Summary of trained immunity studies and lung diseases.
| Cell type(s) | Stimulus | Mechanism(s) | Outcomes | Notes | Study |
|---|---|---|---|---|---|
| Alveolar macrophages (AMs), monocyte-derived AMs (Mo-AMs) | Sequential infections: influenza virus followed by Streptococcus pneumoniae | Influenza leads to depletion of resident AMs through apoptosis, migration, or functional inactivation (‘alveolar macrophage disappearance reaction’). CCR2-dependent monocyte recruitment replenishes the AM niche with Mo-AMs. Mo-AMs undergo IL-6-mediated epigenetic training, enhancing early antibacterial responses. | Improved survival and reduced bacterial burden after secondary pneumococcal infection. Mo-AMs persist but gradually lose protective traits over time. | Trained immunity is transient (~2 months post-influenza). | Aegerter et al., 2020 |
| Resident alveolar macrophages (AMs) | PepO protein from Streptococcus pneumoniae | PepO protein stimulates complement C3 secretion and G-CSF production by AMs, without full activation. Establishes a trained phenotype by enhancing innate bactericidal function against unrelated pathogens. | Central-trained immunity established; increased resistance to bacterial pneumonia without inducing systemic inflammation. | Highlights possibility of trained immunity via non-lethal microbial components. | Xu et al., 2024 |
| Tissue-resident alveolar macrophages (TR-AMs) | Intranasal adenoviral vector administration | Local viral infection stimulates CD8+ T cells to produce IFN-γ, which primes TR-AMs to upregulate MIP-2 and KC chemokines. This enhances neutrophil recruitment to the airways during secondary bacterial infections. Training occurs without monocyte input (local imprinting). | Improved early bacterial clearance upon Streptococcus pneumoniae challenge. | Provides evidence that viral infections can directly induce trained immunity in TR-AMs. | Yao et al., 2018 |
| Mo-AMs replacing TR-AMs (especially in aged lungs) | Aging process, prior respiratory viral infections (influenza) | Aging leads to impaired TR-AM survival and impaired self-renewal capacity. Viral infections exacerbate depletion. CCR2-mediated recruitment of monocytes leads to replacement by Mo-AMs. Mo-AMs show increased glycolysis and a hyper-inflammatory phenotype compared to TR-AMs, contributing to tissue damage and chronic inflammation. | In aged mice, infections cause more severe lung injury due to predominance of glycolytic, inflammatory Mo-AMs rather than quiescent TR-AMs. | Emphasizes metabolic reprogramming (Warburg effect) and its detrimental effects in elderly lung immunity. | Li et al., 2022 |
| Resident airway macrophages | SARS-CoV-2 infection | Persistent chromatin remodeling around type I interferon (IFN-I) response genes, even after viral clearance. Increased accessibility of IRF and STAT transcription factor motifs. Suggests formation of ‘innate immune memory’ following viral pattern recognition. | Enhanced baseline antiviral state, potential impact on future respiratory infections. | Mechanisms still under investigation; likely involve both direct viral sensing and damage signals (DAMPs). | Lercher et al., 2024; Simonis et al., 2025 |
| Natural killer (NK) cells | Viral infections, BCG vaccination | NK cells acquire memory-like properties after infections. Enhanced IFN-γ, IL-1β, and IL-6 production upon secondary stimulation. Primed for faster and stronger responses. | Improved clearance of respiratory viruses; enhanced responses to secondary challenges. | NK cell-trained immunity impacts airway antiviral defense and broader innate immune memory. | Sun et al., 2009; Romee et al., 2012; Kleinnijenhuis et al., 2014 |
| Dendritic cells (DCs) | Cryptococcus neoformans infection, RSV infection | Exposure leads to epigenetic reprogramming of DCs. Increased IFN-γ and pro-inflammatory cytokine production upon secondary encounters. DC-mediated protection relies on cytokine production like IFN-γ, TNF-α, and IL-17a, as well as STAT1 pathway activation. | DCs play a crucial role in trained immunity and protection against reinfection. | Proper activation of DCs is crucial for protective immunity; impaired DC responses can lose protection. | Hole et al., 2019 |
| Dendritic cells (DCs) | Respiratory syncytial virus (RSV) infection | RSV-triggered TSLP induces epigenetic reprogramming in bone marrow-derived DCs, altering cytokine production and upregulating costimulatory molecules. This leads to an enhanced inflammatory phenotype and exacerbated allergic responses. | RSV-induced trained immunity via TSLP alters immune cell responses and can promote allergic diseases. | Innate immune memory may amplify allergic susceptibility and interfere with appropriate antiviral responses. | Hole et al., 2019; Malinczak et al., 2021 |
| Alveolar macrophages (AMs) and epithelial cells | β-glucan exposure, bleomycin-induced injury | β-glucan primes AMs and epithelial cells via soluble mediators. This leads to enhanced efferocytosis, increased SIRT1 expression, and tissue protection by reducing fibrosis and apoptosis. | β-glucan-induced trained immunity protects against injury and fibrosis, particularly in lung epithelial cells. | Enhanced tissue resilience, reduced apoptosis, and increased resistance to lung fibrosis. | Kang et al., 2024 |
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Trained immunity in the lung
eLife 14:e104918.
https://doi.org/10.7554/eLife.104918
