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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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“Classically, major neurotransmitters of The neuron-specific ablation of IL-6 has been demonstrated to increase Ror γ t + Tregs in vivo [42]. the ENS include excitatory molecules such as adenosine triphosphate (ATP), serotonin (5-HT), These studies may provide insight into how the ENS can…”
BackgroundNeuro-immune cell interactions in the regulation of intestinal immune homeostasis
Hou, X., & Artis, D. (2024) · Current Opinion in Gastroenterology · doi:10.1097/mog.0000000000001065 · Cited by 10
Gut neuropeptide involvement in Parkinson’s disease
Templeton, H., Tobet, S. A., & Schwerdtfeger, L. (2025) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00383.2024 · Cited by 11
The Role of the Gut-Brain Axis in Diseases
Chen, J. W., Xu, Y., & Cao, P. (2025) · Physiology · doi:10.1152/physiol.00016.2025 · Cited by 13
The environmental pollutant 3-methyl-4-nitrophenol reduces the regulatory T cells in the intestine
Hu, S., Liu, H., Tao, S., Wang, Y., Wang, S., Liao, Y., Zheng, P., & Yang, P. (2022) · Toxicology · doi:10.1016/j.tox.2022.153356 · Cited by 9
Neuroimmune crosstalk in the gut and liver
Teratani, T., Mikami, Y., & Kanai∥, T. (2022) · International Immunology · doi:10.1093/intimm/dxac033 · Cited by 9
Zhang, M., Shan, K., Song, S., Bai, J., Jiang, P., Zhao, D., Ke, W., Zhou, G., & Li, C. (2023) · Food Frontiers · doi:10.1002/fft2.239 · Cited by 9
Su, Y., Ma, G., Zheng, Y., Qin, J., Li, X., Ge, Q., Sun, H., & Liu, B. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24129915 · Cited by 9
Schill, E. M., Joyce, E. L., Floyd, A. N., Udayan, S., Rusconi, B. A., Gaddipati, S., Barrios, B. E., John, V., Kaye, M. E., Kulkarni, D. H., et al. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1268909 · Cited by 8
The role of reactive enteric glia‐macrophage interactions in acute and chronic inflammation
Schneider, R., Schneider, L. H., Hamza, E., Leven, P., & Wehner, S. (2024) · Neurogastroenterology & Motility · doi:10.1111/nmo.14947 · Cited by 8
Ragab, M., Schlichting, H., Hicken, M., Mester, P., Hirose, M., de Almeida, L. N., Christiansen, L., Ibrahim, S. M., Tews, H. C., Divanovic, S., et al. (2024) · Scientific Reports · doi:10.1038/s41598-024-63730-4 · Cited by 8
“However, published research as well as analyses in the current study indicate that intraepithelial lymphocytes and enteric neurons, rather than intestinal epithelial cells, are the primary sources of IL6 production 48,49 .”
Association of Chronic Inflammation-Associated Cancer With Cytokines
Nakase, H., & Shimomori, Y. (2025) · Cureus · doi:10.7759/cureus.92239 · Cited by 8
“Immune evasion: IL-6 can create an immunosuppressive environment by promoting the differentiation of regulatory T cells (Tregs) and inhibiting the activity of cytotoxic T cells, which are essential for tumor immune surveillance [40,41].”
Naim, G., Romano-Zadaka, H., Amidror, S., Levy, D. J., Cohen, A., Sochen, C., Gilberg, H., Farah, N., Rudenko, V., Yarden‐Rabinowitz, Y., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-64995-7 · Cited by 8
Feuerer, M., Gray, D. H. D., Rankin, L. C., Schmidleithner, L., & Liston, A. (2026) · Annual Review of Immunology · doi:10.1146/annurev-immunol-082924-092651 · Cited by 8
Ahn, S. Y., Sung, D. K., Chang, Y. S., & Park, W. S. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23126601 · Cited by 7
Artesunate targets cellular metabolism to regulate the Th17/Treg cell balance
Chen, K., Tang, L., & Nong, X. (2023) · Inflammation Research · doi:10.1007/s00011-023-01729-9 · Cited by 7
“This plasticity is promoted by cytokines such as IL-6, IL-1, TNF-α, and IL-23, which enable Treg cells to respond to tissue-specific chemical inducers and migrate to target sites to regulate immune responses [48].”
BackgroundDevelopment of a non-invasive bioassay for adiponectin target engagement in mice
Tang, J., Lei, Y., Pignalosa, A., Hsu, H. H., Sater, A. A. A., & Sweeney, G. (2024) · iScience · doi:10.1016/j.isci.2024.110994 · Cited by 6
The role of the enteric nervous system in the pathogenesis of Clostridioides difficile infection
Costa, D. V. D. S., Thomasi, B. B. D. M., Brito, G. A. D. C., Gulbransen, B. D., & Warren, C. A. (2025) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-025-01071-x · Cited by 6
Jiang, J., Liu, X., Zhang, Y., Kong, Y., Luo, Q., Hou, Y., Li, L., Liu, S., Tao, Q., Lin, S., et al. (2025) · Journal of Investigative Dermatology · doi:10.1016/j.jid.2025.07.018 · Cited by 6
Yan, B., Zheng, X., Lu, D., Li, T., Chen, X., Shao, Z., & Fu, T. (2025) · The ISME Journal · doi:10.1093/ismejo/wraf175 · Cited by 6
“Furthermore, research has shown that enteric neurons modulate Th17 cell differ entiation through various mechanisms [44].”
Fecal metabolomics in Crohn’s disease reveal N-Acetylglutamine as a Th17/Treg modulator
Han, M., Dong, X., Zhao, R., Hu, X., Li, D., Yan, X., Liu, Y., Du, Q., & Li, M. (2025) · Molecular Immunology · doi:10.1016/j.molimm.2025.11.012 · Cited by 6
The role of gut microbiota in neuropathic pain: insights into immune mechanisms
Gong, Z., Zou, J., Fang, Y., Li, J., Luo, Y., Xue, Q., Yu, B., Hua, B., & Liu, Z. (2025) · The Journal of Headache and Pain · doi:10.1186/s10194-025-02260-4 · Cited by 10
“…Clostridium ramosum , a potent inducer of RORγ+ Tregs [245], augments Treg populations within the intestinal milieu by decreasing neuronal cell body density and reducing nerve fiber caliber in the myenteric plexus, thereby attenuating the inhibitory influence of enteric neurons on Tregs [246].”
Regulation of Host Immunity by the Gut Microbiota
Partney, H., & Yissachar, N. (2022) · Progress in inflammation research · doi:10.1007/978-3-030-91051-8_4 · Cited by 6
Linking the gut microbiome to microglial activation in opioid use disorder
Antoine, D., Venigalla, G., Truitt, B., & Roy, S. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.1050661 · Cited by 6
“IL-6 is produced by enteric neurons in a regulatory manner to mediate the number and phenotype of microbe-responsive regulatory T (Treg) cells in the gut (Yan et al., 2021).”
BackgroundZhao, Y., Zhang, G., Yu, F., Bai, F., Ai, C., Zhou, D., Zhou, D., Xu, X., Liu, H., Duan, J., et al. (2025) · Chemical Engineering Journal · doi:10.1016/j.cej.2025.161354 · Cited by 5
Tissue-resident regulatory T cells: modulators of local immunity
Shi, Y., Wang, L., Bao, C., Wang, G., & Sun, Z. (2026) · Trends in Immunology · doi:10.1016/j.it.2025.12.001 · Cited by 5
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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