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Interleukin-6 produced by enteric neurons regulates the number and phenotype of microbe-responsive regulatory T cells in the gut
Open accessAbstract
The immune and enteric nervous (ENS) systems monitor the frontier with commensal and pathogenic microbes in the colon. We investigated whether FoxP3+ regulatory T (Treg) cells functionally interact with the ENS. Indeed, microbe-responsive RORγ+ and Helios+ subsets localized in close apposition to nitrergic and peptidergic nerve fibers in the colon lamina propria (LP). Enteric neurons inhibited in vitro Treg (iTreg) differentiation in a cell-contact-independent manner. A screen of neuron-secreted factors revealed a role for interleukin-6 (IL-6) in modulating iTreg formation and their RORγ+ proportion. Colonization of germfree mice with commensals, especially RORγ+ Treg inducers, broadly diminished colon neuronal density. Closing the triangle, conditional ablation of IL-6 in neurons increased total Treg cells but decreased the RORγ+ subset, as did depletion of two ENS neurotransmitters. Our findings suggest a regulatory circuit wherein microbial signals condition neuronal density and activation, thus tuning Treg cell generation and immunological tolerance in the gut.
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“This supports the hypothesis [39] that immune dysregulation constitutes a shared etiological mechanism in both neuropsychiatric and digestive pathologies.”
From The hidden genetic and microbial networks connecting neuropsychiatric and digestive disorders (2025) · cites this paper as [39]
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“While prior studies implicate T-cell activity and immune signaling in individual conditions, accumulating evidence suggests their functional interplay with gut-innervating neurons in regulating immune tolerance and microbial homeostasis [39], reinforcing their integrative role as elucidated in this study.”
From The hidden genetic and microbial networks connecting neuropsychiatric and digestive disorders (2025) · cites this paper as [39]
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Metadata
- Authors
- Yan, Y., Ramanan, D., Rozenberg, M., McGovern, K., Rastelli, D., Vijaykumar, B., Yaghi, O., Voisin, T., Mosaheb, M., Chiu, I., Itzkovitz, S., Rao, M., Mathis, D., & Benoist, C.
- Affiliations
- Harvard University (US)
- Weizmann Institute of Science (IL)
- Boston Children's Hospital (US)
- Corresponding author
- Benoist, Christophe
- ORCID
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2021-03
- Volume
- 54
- Issue
- 3
- Pages
- 499-513.e5
- ISSN
- 1074-7613 (ISSN-L)
- PMC
- PMC8133394
- OpenAlex
- W3135830535
- Cited by
- 165
- References
- 76
- Citations by year
- 2026: 32 · 2025: 42 · 2024: 28 · 2023: 22 · 2022: 25 · 2021: 15
- FWCI
- 8.38
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 373 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Immunity (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIAID
- NIDDK
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Life Sciences › Immunology and Microbiology › Immunology › IL-33, ST2, and ILC Pathways
- Keywords
- interleukin-6, enteric nervous system, regulatory T cells, Foxp3+ regulatory T cells, gut microbiota, nitrergic neurons, peptidergic neurons, germ-free mice, immune tolerance
- MeSH terms
- Gastrointestinal Microbiome, Animals, Cell Differentiation, Cells, Cultured, Intestines, Mice, Inbred C57BL, Neurons, Phenotype, Interleukin-6, T-Lymphocyte Subsets, Enteric Nervous System, Mice, Knockout, Neurotransmitter Agents, Coculture Techniques, Cell Proliferation, T-Lymphocytes, Regulatory, Mice, Nuclear Receptor Subfamily 1, Group F, Member 3
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