The DOI matches its Crossref record; 76 of the 76 references it cites were found in a registry or an index.
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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Full-length RNA-seq from single cells using Smart-seq2
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Induction of Colonic Regulatory T Cells by Indigenous Clostridium Species
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Regulatory T cells: mechanisms of differentiation and function
Josefowicz, S. Z., Lu, L.-F., & Rudensky, A. Y. (2012) · Annual Review of Immunology · doi:10.1146/annurev.immunol.25.022106.141623 · Cited by 2,866
Molecular Architecture of the Mouse Nervous System
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IL-6 as a keystone cytokine in health and disease
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TGF-β-induced Foxp3 inhibits TH17 cell differentiation by antagonizing RORγt function
Zhou, L., Lopes, J. E., Chong, M. M. W., Ivanov, I. I., Min, R., Victora, G. D., Shen, Y., Du, J., Rubtsov, Y. P., Rudensky, A. Y., et al. (2008) · Nature · doi:10.1038/nature06878 · Cited by 1,928
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Self-citationCritical role of the gut microbiota in immune responses and cancer immunotherapy
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“These factors are modulated by gut microbial signals [167–170].”
Background
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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