Brain regulatory T cells suppress astrogliosis and potentiate neurological recovery
Abstract
In addition to maintaining immune tolerance, FOXP3 + regulatory T (T reg ) cells perform specialized functions in tissue homeostasis and remodelling 1,2 . However, the characteristics and functions of brain T reg cells are not well understood because there is a low number of T reg cells in the brain under normal conditions. Here we show that there is massive accumulation of T reg cells in the mouse brain after ischaemic stroke, and this potentiates neurological recovery during the chronic phase of ischaemic brain injury. Although brain T reg cells are similar to T reg cells in other tissues such as visceral adipose tissue and muscle 3-5 , they are apparently distinct and express unique genes related to the nervous system including Htr7, which encodes the serotonin receptor 5-HT 7 . The amplification of brain T reg cells is dependent on interleukin (IL)-2, IL-33, serotonin and T cell receptor recognition, and infiltration into the brain is driven by the chemokines CCL1 and CCL20. Brain T reg cells suppress neurotoxic astrogliosis by producing amphiregulin, a low-affinity epidermal growth factor receptor (EGFR) ligand. Stroke is a leading cause of neurological disability, and there are currently few effective recovery methods other than rehabilitation during the chronic phase. Our findings suggest that T reg cells and their products may provide therapeutic opportunities for neuronal protection against stroke and neuroinflammatory diseases.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Treg cell-derived amphiregulin (Areg) promotes repair after acute tissue injury.
“Production of amphiregulin (Areg) by regulatory T (Treg) cells promotes repair after acute tissue injury.”
From Amphiregulin from regulatory T cells promotes liver fibrosis and insulin resistance in non-alcoholic steatohepatitis (2024) · cites this paper as [27]
Treg cells protect from epithelial cell injury by both interacting with immune cells to suppress inflammation and by producing epithelial growth factors that signal to non-immune cells.
“Together, these studies suggest that Treg cells protect from epithelial cell injury by both interacting with immune cells to suppress inflammation and by producing epithelial growth factors that signal to non-immune cells.”
From Amphiregulin from regulatory T cells promotes liver fibrosis and insulin resistance in non-alcoholic steatohepatitis (2024) · cites this paper as [27]
TCR signaling is thought to contribute to Treg cell accumulation in the brain and VAT.
“As TCR signaling is thought to contribute to Treg cell accumulation in the brain and VAT 27,35”
From Amphiregulin from regulatory T cells promotes liver fibrosis and insulin resistance in non-alcoholic steatohepatitis (2024) · cites this paper as [27]
Cites
Neurotoxic reactive astrocytes are induced by activated microglia
Liddelow, S. A., Guttenplan, K. A., Clarke, L. E., Bennett, F. C., Bohlen, C. J., Schirmer, L., Bennett, M. L., Münch, A. E., Chung, W.-S., Peterson, T. C., et al. (2017) · Nature · doi:10.1038/nature21029 · Cited by 7,971 · see citing works
Astrocyte scar formation aids central nervous system axon regeneration
Anderson, M. A., Burda, J. E., Ren, Y., Ao, Y., O’Shea, T. M., Kawaguchi, R., Coppola, G., Khakh, B. S., Deming, T. J., & Sofroniew, M. V. (2016) · Nature · doi:10.1038/nature17623 · Cited by 1,851 · see citing works
A function for interleukin 2 in Foxp3-expressing regulatory T cells
Fontenot, J. D., Rasmussen, J. P., Gavin, M. A., & Rudensky, A. Y. (2005) · Nature Immunology · doi:10.1038/ni1263 · Cited by 1,819 · see citing works
Thornton, A. M., Korty, P. E., Tran, D. Q., Wohlfert, E. A., Murray, P. E., Belkaid, Y., & Shevach, E. M. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.0904028 · Cited by 1,382 · see citing works
A Special Population of Regulatory T Cells Potentiates Muscle Repair
Burzyn, D., Kuswanto, W., Kolodin, D., Shadrach, J. L., Cerletti, M., Jang, Y., Sefik, E., Tan, T. G., Wagers, A. J., Benoist, C., et al. (2013) · Cell · doi:10.1016/j.cell.2013.10.054 · Cited by 1,234 · see citing works
TCR Transgenic Mice Reveal Stepwise, Multi-site Acquisition of the Distinctive Fat-Treg Phenotype
Li, C., DiSpirito, J. R., Zemmour, D., Spallanzani, R. G., Kuswanto, W., Benoist, C., & Mathis, D. (2018) · Cell · doi:10.1016/j.cell.2018.05.004 · Cited by 231 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Immune responses to stroke: mechanisms, modulation, and therapeutic potential.
Iadecola, C., Buckwalter, M. S., & Anrather, J. (2020) · Journal of Clinical Investigation · doi:10.1172/jci135530 · Cited by 853 · see citing works
Guidelines for the use of flow cytometry and cell sorting in immunological studies (third edition)
Cossarizza, A., Chang, H., Radbruch, A., Abrignani, S., Addo, R., Akdis, M., Andrä, I., Andreata, F., Annunziato, F., Arranz, E., et al. (2021) · European Journal of Immunology · doi:10.1002/eji.202170126 · Cited by 531 · see citing works
Tryptophan metabolism and gut-brain homeostasis
Roth, W., Zadeh, K., Vekariya, R., Ge, Y., & Mohamadzadeh, M. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22062973 · Cited by 519 · see citing works
Microglia Require CD4 T Cells to Complete the Fetal-to-Adult Transition
Pasciuto, E., Burton, O. T., Roca, C. P., Lagou, V., Rajan, W. D., Theys, T., Mancuso, R., Tito, R. Y., Kouser, L., Callaerts-Vegh, Z., et al. (2020) · Cell · doi:10.1016/j.cell.2020.06.026 · Cited by 368 · see citing works
Gut-licensed IFNγ+ NK cells drive LAMP1+TRAIL+ anti-inflammatory astrocytes
Sanmarco, L. M., Wheeler, M. A., Gutiérrez-Vázquez, C., Polonio, C. M., Linnerbauer, M., Pinho-Ribeiro, F. A., Li, Z., Giovannoni, F., Batterman, K. V., Scalisi, G., et al. (2021) · Nature · doi:10.1038/s41586-020-03116-4 · Cited by 331 · see citing works
Tissue regulatory T cells: regulatory chameleons
Muñoz-Rojas, A. R., & Mathis, D. (2021) · Nature Reviews Immunology · doi:10.1038/s41577-021-00519-w · Cited by 281 · see citing works
Delacher, M., Imbusch, C. D., Hotz-Wagenblatt, A., Mallm, J.-P., Bauer, K., Simon, M., Riegel, D., Rendeiro, A. F., Bittner, S., Sanderink, L., et al. (2020) · Immunity · doi:10.1016/j.immuni.2019.12.002 · Cited by 261 · see citing works
Systemic factors as mediators of brain homeostasis, ageing and neurodegeneration
Pluvinage, J. V., & Wyss-Coray, T. (2020) · Nature Reviews Neuroscience · doi:10.1038/s41583-019-0255-9 · Cited by 191 · see citing works
Delacher, M., Simon, M., Sanderink, L., Hotz-Wagenblatt, A., Wuttke, M., Schambeck, K., Schmidleithner, L., Bittner, S., Pant, A., Ritter, U., et al. (2021) · Immunity · doi:10.1016/j.immuni.2021.03.007 · Cited by 164 · see citing works
Aging and Neurodegenerative Disease: Is the Adaptive Immune System a Friend or Foe?
Mayne, K., White, J. A., McMurran, C. E., Rivera, F. J., & de la Fuente, A. G. (2020) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2020.572090 · Cited by 167 · see citing works
The aryl hydrocarbon receptor and the gut–brain axis
Barroso, A., Mahler, J. V., Fonseca-Castro, P. H., & Quintana, F. J. (2021) · Cellular & Molecular Immunology · doi:10.1038/s41423-020-00585-5 · Cited by 152 · see citing works
Savage, T. M., Fortson, K. T., de los Santos-Alexis, K., Oliveras-Alsina, A., Rouanne, M., Rae, S. S., Gamarra, J. R., Shayya, H., Kornberg, A., Cavero, R., et al. (2024) · Immunity · doi:10.1016/j.immuni.2024.01.009 · Cited by 115 · see citing works
The contribution of the peripheral immune system to neurodegeneration
Berriat, F., Lobsiger, C. S., & Boillée, S. (2023) · Nature Neuroscience · doi:10.1038/s41593-023-01323-6 · Cited by 87 · see citing works
Kamila, P., Kar, K., Chowdhury, S., Chakraborty, P., Dutta, R., S, S., Singh S, A., & Prajapati, B. G. (2025) · IBRO Neuroscience Reports · doi:10.1016/j.ibneur.2025.05.005 · Cited by 90 · see citing works
Xie, Y., Zou, X., Han, J., Zhang, Z., Feng, Z., Ouyang, Q., Hua, S., Liu, Z., Li, C., Cai, Y., et al. (2022) · Experimental Neurology · doi:10.1016/j.expneurol.2022.114081 · Cited by 80 · see citing works
Regulation of the alveolar regenerative niche by amphiregulin-producing regulatory T cells
Kaiser, K. A., Loffredo, L. F., Santos-Alexis, K. D. L., Ringham, O. R., & Arpaia, N. (2023) · Journal of Experimental Medicine · doi:10.1084/jem.20221462 · Cited by 79 · see citing works
Saito, M., Fujinami, Y., Ono, Y., Ohyama, S., Fujioka, K., Yamashita, K., Inoue, S., & Kotani, J. (2021) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2020.11.010 · Cited by 66 · see citing works
Yang, J., Cao, L.-L., Wang, X.-P., Guo, W., Guo, R.-B., Sun, Y.-Q., Xue, T.-F., Cai, Z.-Y., Ji, J., Cheng, H., et al. (2021) · Cell Death & Disease · doi:10.1038/s41419-020-03310-2 · Cited by 73 · see citing works
Ikeno, Y., Ohara, D., Takeuchi, Y., Watanabe, H., Kondoh, G., Taura, K., Uemoto, S., & Hirota, K. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.584048 · Cited by 62 · see citing works
Li, L., Ni, L., Heary, R. F., & Elkabes, S. (2020) · Journal of Neuroinflammation · doi:10.1186/s12974-020-01748-x · Cited by 34 · see citing works
Ohyagi, M., Ito, M., Iizuka-Koga, M., Mise-Omata, S., & Yoshimura, A. (2025) · Nature Communications · doi:10.1038/s41467-025-64503-x · Cited by 24 · see citing works
Self-citationInsight Into Regulatory T Cells in Sepsis-Associated Encephalopathy
Gao, Y.-L., Liu, Y.-C., Zhang, X., Shou, S.-T., & Chai, Y.-F. (2022) · Frontiers in Neurology · doi:10.3389/fneur.2022.830784 · Cited by 11 · see citing works
- Authors
- Ito, M., Komai, K., Mise-Omata, S., Iizuka-Koga, M., Noguchi, Y., Kondo, T., Sakai, R., Matsuo, K., Nakayama, T., Yoshie, O., Nakatsukasa, H., Chikuma, S., Shichita, T., & Yoshimura, A.
- Affiliations
- Keio University (JP)
- Kindai University (JP)
- Corresponding author
- Ito, Minako
- Yoshimura, Akihiko
- ORCID
- Venue
- Nature
- Published
- 2019-01
- Volume
- 565
- Issue
- 7738
- Pages
- 246-250
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2906480617
- Cited by
- 784
- References
- 6
- Citations by year
- 2026: 72 · 2025: 125 · 2024: 121 · 2023: 112 · 2022: 116 · 2021: 120 · 2020: 72 · 2019: 45
- FWCI
- 26.76
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Japan Society for the Promotion of Science (20K20384, 16K09867, 17K19571, 18K15129, 17H06175, 17H05096)
- Core Research for Evolutional Science and Technology
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- Foxp3, ischemic stroke, astrocyte activation, neurological recovery, amphiregulin, 5-HT7 receptor, interleukin-2, IL-33, CCL1, CCL20, neuroinflammation, epidermal growth factor receptor ligands, neuroprotection
- MeSH terms
- Neuroprotection, Interleukin-33, Animals, Astrocytes, Brain, Cell Movement, Brain Ischemia, Gliosis, Interleukin-2, Male, Mice, Inbred C57BL, Receptors, Antigen, T-Cell, Receptors, Serotonin, Serotonin, Signal Transduction, Interleukin-6, Cell Proliferation, T-Lymphocytes, Regulatory, STAT3 Transcription Factor, Mice, Receptors, CCR, Chemokine CCL1, Chemokine CCL20
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
