NOD2 modulates immune tolerance via the GM-CSF–dependent generation of CD103 + dendritic cells
Open accessAbstract
Four decades ago, it was identified that muramyl dipeptide (MDP), a peptidoglycan-derived bacterial cell wall component, could display immunosuppressive functions in animals through mechanisms that remain unexplored. We sought to revisit these pioneering observations because mutations in NOD2 , the gene encoding the host sensor of MDP, are associated with increased risk of developing the inflammatory bowel disease Crohn’s disease, thus suggesting that the loss of the immunomodulatory functions of NOD2 could contribute to the development of inflammatory disease. Here, we demonstrate that intraperitoneal (i.p.) administration of MDP triggered regulatory T cells and the accumulation of a population of tolerogenic CD103 + dendritic cells (DCs) in the spleen. This was found to occur not through direct sensing of MDP by DCs themselves, but rather via the production of the cytokine GM-CSF, another factor with an established regulatory role in Crohn’s disease pathogenesis. Moreover, we demonstrate that populations of CD103-expressing DCs in the gut lamina propria are enhanced by the activation of NOD2, indicating that MDP sensing plays a critical role in shaping the immune response to intestinal antigens by promoting a tolerogenic environment via manipulation of DC populations.
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NOD2 stimulation by MDP and its analogs can alter host immunity through multiple pathways, including macrophage activation for tumor clearance, epigenetic reprogramming of monocytes, generation of conventional type 1 dendritic cells, and dendritic cell priming for cross-presentation to CD8+ T cells.
“our findings corroborate a wealth of emerging evidence that NOD2 stimulation by MDP and its analogs can alter host immunity through multiple pathways including the direct activation of macrophages for tumor cell clearance (39), epigenetic reprogramming of monocytes (40, 41), generation of conventional type 1 dendritic cells (42), and priming of dendritic cells for cross-presentation to CD8+ T cell”
From <i>Enterococcus</i> peptidoglycan remodeling promotes checkpoint inhibitor cancer immunotherapy (2021) · cites this paper as [42]
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<i>Enterococcus</i> peptidoglycan remodeling promotes checkpoint inhibitor cancer immunotherapy
Griffin, M. E., Espinosa, J., Becker, J. L., Luo, J.-D., Carroll, T. S., Jha, J. K., Fanger, G. R., & Hang, H. C. (2021) · Science · doi:10.1126/science.abc9113 · Cited by 366 · see citing works
- Authors
- Prescott, D., Maisonneuve, C., Yadav, J., Rubino, S. J., Girardin, S. E., & Philpott, D. J.
- Affiliations
- University of Toronto (CA)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2020-04-29
- Volume
- 117
- Issue
- 20
- Pages
- 10946-10957
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC7245098
- OpenAlex
- W3023664370
- Cited by
- 26
- References
- 63
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 5 · 2023: 5 · 2022: 3 · 2021: 5 · 2020: 1
- FWCI
- 1.22
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Gouvernement du Canada | Canadian Institutes of Health Research (FDN-14333, MOP-12353)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- NOD2, muramyl dipeptide, peptidoglycan sensing, immune tolerance, regulatory T cells, CD103+ dendritic cells, GM-CSF, Crohn's disease, inflammatory bowel disease, tolerogenic dendritic cells, lamina propria, intestinal immunity, immunosuppression
- MeSH terms
- Acetylmuramyl-Alanyl-Isoglutamine, Animals, Crohn Disease, Dendritic Cells, Humans, Immune Tolerance, Mice, Inbred C57BL, Mutation, Antigens, CD, Granulocyte-Macrophage Colony-Stimulating Factor, Cytokines, Mice, Knockout, Integrin alpha Chains, T-Lymphocytes, Regulatory, Mice, Nod2 Signaling Adaptor Protein
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