Resident memory macrophages and trained innate immunity at barrier tissues
- McMaster Immunology Research Centre, Department of Medicine, M.G. DeGroote Institute for Infectious Disease Research, McMaster University, Canada
Figures
Figure 1
Induction of innate immune memory in tissue-resident macrophages following local and systemic immunological exposure.
Following local immunological exposure to immune stimuli, including adenovirus-vectored vaccine, the priming, but not the maintenance, of memory alveolar macrophages (AMs) requires help from effector CD8+ T cells via IFN-γ production and is contact-dependent. Tissue-resident macrophages at barrier sites trained by vaccines or microbial components causing limited inflammation are primarily of tissue-residential/embryonic origin. Those resulted from more potent stimulation, such as robust infection or severe inflammation, are monocyte-derived AMs. Thus, the degree of inflammation following local exposure can lead to various outcomes, from no replacement to partial or complete replacement of lung tissue-resident macrophages by recruited circulating monocytes. On the other hand, following systemic immunological exposure, such as cutaneous Bacillus Calmette-Guérin (BCG) vaccination, BCG bacilli disseminate to gut-associated tissues and lead to a time-dependent changes in the gut microbiota and barrier permeability, and metabolomic changes in the gut, serum, and lung. This results in the induction of memory AMs and TII in the lung. Monocytes play a relatively minor role in the development and maintenance of innate immune memory in lung tissue-resident macrophages, particularly AMs following systemic immunological exposure. Created in https://BioRender.com/478t8uu.
Figure 2
Illustrated paradigms of conventional vaccines, nontarget-specific trained innate immunity (TII)-based vaccines/agents, and next-generation vaccine strategies.
Conventional vaccines are primarily designed to target pathogen-specific antigens, leading to antigen-dependent induction of adaptive immune memory and protection. However, some of these vaccines are also capable of a degree of TII. In comparison, nontarget-specific trained immunity-based vaccines or immune agents aim to induce innate immune memory in innate cells and provide rapid, nonspecific (antigen-independent) broad innate immune protection against a variety of heterologous infections. Such strategies can be used for emergent deployment at the onset of pandemics before target-specific vaccines become available. On the other hand, to better control current infectious threats and prepare for future pandemics, the next-generation vaccine strategies should be not only target pathogen-specific but also TII-based, aiming to induce robust and long-lasting innate and adaptive immune memory capable of protection against both the target pathogen and unrelated pathogens via both nonspecific and specific protective mechanisms. One such strategy is respiratory mucosal immunization with a viral-vectored multi-antigenic vaccine for induction of tripartite mucosal immunity consisting of trained innate immunity, mucosal antibody responses, and tissue-resident T cell immunity. Created using BioRender.com.
Tables
Table 1
The outcome of systemic and/or local immunological exposure-induced trained innate immunity (TII) in different pathological conditions.
| Barrier tissue site | Pathology | Outcome | References |
|---|---|---|---|
| Lung | Pneumonia | Protection | Kang et al., 2024a; Kang et al., 2023; Yao et al., 2018; Zahalka et al., 2022 |
| Promotes disease | Roquilly et al., 2020 | ||
| TB | Protection | Bickett et al., 2020; D’Agostino et al., 2020; Jeyanathan et al., 2022b; Moorlag et al., 2020 | |
| Influenza | Protection | Kaufmann et al., 2022; Khan et al., 2025; Lercher et al., 2024 | |
| Promotes disease | Li et al., 2022a | ||
| COVID-19 | Protection | Afkhami et al., 2022; Hilligan et al., 2022; Oyesola et al., 2023; Zhang et al., 2022 | |
| Helminth | Protection | Chen et al., 2014 | |
| Lung cancer | Protection | Wang et al., 2023 | |
| Genital tract | Bladder cancer | Protection | Daman et al., 2025; Jurado et al., 2025 |
| Skin | Staph infection | Protection | Chan et al., 2018; Chan et al., 2017; Feuerstein et al., 2020 |
| GI tract | Salmonella | Protection | Ahrends et al., 2021 |
| Peritoneal cavity | Staph infection | Protection | Yoshida et al., 2015 |
| Peritonitis | Protection | Ciarlo et al., 2020 | |
| Endometriosis | Protection | Jeljeli et al., 2020 | |
| Oral cavity | Periodontitis | Promotes disease | Li et al., 2022b |
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Resident memory macrophages and trained innate immunity at barrier tissues
eLife 14:e106549.
https://doi.org/10.7554/eLife.106549
