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Different tissue phagocytes sample apoptotic cells to direct distinct homeostasis programs
Open accessAbstract
Recognition and removal of apoptotic cells by professional phagocytes, including dendritic cells and macrophages, preserves immune self-tolerance and prevents chronic inflammation and autoimmune pathologies. The diverse array of phagocytes that reside within different tissues, combined with the necessarily prompt nature of apoptotic cell clearance, makes it difficult to study this process in situ. The full spectrum of functions executed by tissue-resident phagocytes in response to homeostatic apoptosis, therefore, remains unclear. Here we show that mouse apoptotic intestinal epithelial cells (IECs), which undergo continuous renewal to maintain optimal barrier and absorptive functions, are not merely extruded to maintain homeostatic cell numbers, but are also sampled by a single subset of dendritic cells and two macrophage subsets within a well-characterized network of phagocytes in the small intestinal lamina propria. Characterization of the transcriptome within each subset before and after in situ sampling of apoptotic IECs revealed gene expression signatures unique to each phagocyte, including macrophage-specific lipid metabolism and amino acid catabolism, and a dendritic-cell-specific program of regulatory CD4+ T-cell activation. A common 'suppression of inflammation' signature was noted, although the specific genes and pathways involved varied amongst dendritic cells and macrophages, reflecting specialized functions. Apoptotic IECs were trafficked to mesenteric lymph nodes exclusively by the dendritic cell subset and served as critical determinants for the induction of tolerogenic regulatory CD4+ T-cell differentiation. Several of the genes that were differentially expressed by phagocytes bearing apoptotic IECs overlapped with susceptibility genes for inflammatory bowel disease. Collectively, these findings provide new insights into the consequences of apoptotic cell sampling, advance our understanding of how homeostasis is maintained within the mucosa and set the stage for development of novel therapeutics to alleviate chronic inflammatory diseases such as inflammatory bowel disease.
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“CD103+ DCs selectively carry apoptotic intestinal epithelial cells to mesenteric lymph nodes, which function as critical determinants to induce tolerogenic CD4+ regulatory T-cell differentiation in mice [161].”
From Immune Clearance of Senescent Cells to Combat Ageing and Chronic Diseases (2020) · cites this paper as [161]
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“CD24+ DCs generally exert their removal function via T-cell regulation.”
From Immune Clearance of Senescent Cells to Combat Ageing and Chronic Diseases (2020) · cites this paper as [161]
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Metadata
- Authors
- Cummings, R. J., Barbet, G., Bongers, G., Hartmann, B. M., Gettler, K., Muniz, L., Furtado, G. C., Cho, J., Lira, S. A., & Blander, J. M.
- Affiliations
- Icahn School of Medicine at Mount Sinai (US)
- Yale University (US)
- Tisch Cancer Institute (US)
- Corresponding author
- Blander, J. Magarian
- Venue
- Nature
- Published
- 2016-11
- Volume
- 539
- Issue
- 7630
- Pages
- 565-569
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5807003
- OpenAlex
- W2556519132
- Cited by
- 228
- References
- 35
- Citations by year
- 2026: 23 · 2025: 20 · 2024: 22 · 2023: 21 · 2022: 26 · 2021: 25 · 2020: 32 · 2019: 21 · 2018: 17 · 2017: 21
- FWCI
- 11.92
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Rutgers University Community Repository (Rutgers University) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Crohn's and Colitis Foundation (294024)
- National Institutes of Health (5r01dk092235-06, 2T32A1007605-11, DK072201)
- National Cancer Institute (R01CA161373)
- National Institute of Allergy and Infectious Diseases (HHSN272201000054C, U19AI117873, R01AI095245, R01AI123284)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01-DK092235, R01DK111862, T32DK007792, P01DK072201, U01DK062429, U01DK062422, R01DK110352)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (T32HD007149)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- efferocytosis, intestinal epithelial cells, dendritic cells, macrophage subsets, regulatory T cells, self-tolerance, mesenteric lymph nodes, tissue homeostasis, lipid metabolism, amino acid catabolism, chronic intestinal inflammation, autoimmunity
- MeSH terms
- Amino Acids, Animals, Cell Differentiation, Cell Movement, Dendritic Cells, Epithelial Cells, Female, Homeostasis, Inflammation, Intestinal Mucosa, Lymph Nodes, Lymphocyte Activation, Macrophages, Male, Phagocytes, Transcription, Genetic, Inflammatory Bowel Diseases, CD4-Positive T-Lymphocytes, Antigens, CD, Apoptosis, Integrin alpha Chains, Lipid Metabolism, T-Lymphocytes, Regulatory, Mice
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