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Regulatory T cells promote myelin regeneration in the central nervous system
Open accessAbstract
Regeneration of myelin is a dynamic, yet enigmatic process. Dombrowski et al. uncover a central role for regulatory T (Treg) cells in driving oligodendrocyte differentiation, in part via CCN3, a novel factor in Treg function and oligodendrocyte biology. This identifies Treg cells as key cellular players in efficient remyelination. Regeneration of CNS myelin involves differentiation of oligodendrocytes from oligodendrocyte progenitor cells. In multiple sclerosis, remyelination can fail despite abundant oligodendrocyte progenitor cells, suggesting impairment of oligodendrocyte differentiation. T cells infiltrate the CNS in multiple sclerosis, yet little is known about T cell functions in remyelination. We report that regulatory T cells (Treg) promote oligodendrocyte differentiation and (re)myelination. Treg-deficient mice exhibited substantially impaired remyelination and oligodendrocyte differentiation, which was rescued by adoptive transfer of Treg. In brain slice cultures, Treg accelerated developmental myelination and remyelination, even in the absence of overt inflammation. Treg directly promoted oligodendrocyte progenitor cell differentiation and myelination in vitro. We identified CCN3 as a Treg-derived mediator of oligodendrocyte differentiation and myelination in vitro. These findings reveal a new regenerative function of Treg in the CNS, distinct from immunomodulation. Although the cells were originally named 'Treg' to reflect immunoregulatory roles, this also captures emerging, regenerative Treg functions.
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“In a recent study, Dombrowski and colleagues demonstrated that T reg cells promote oligodendrocyte differentiation and myelin repair counteracting the well-known pro-inflammatory and cytotoxic effects of T h 1, T h 17, and cytotoxic T cell subpopulations (Dombrowski et al., 2017).”
From Cuprizone‐induced demyelination triggers a CD8‐pronounced T cell recruitment (2021) · cites this paper as Dombrowski et al., 2017
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“In principle, both detrimental and reparative effects of CD3 + lymphocytes have been demonstrated in MS animal models including the delay of, and promotion of remyelination (Baxi et al., 2015;Bieber, Kerr, & Rodriguez, 2003;Dombrowski et al., 2017;Wagner, Roqué, Mileur, Liggitt, & Goverman, 2020;Wang et al., 2010).”
From Cuprizone‐induced demyelination triggers a CD8‐pronounced T cell recruitment (2021) · cites this paper as Dombrowski et al., 2017
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“For example, Treg cells can promote oligodendrocyte progenitor cell differentiation and, thereby, myelin regeneration in the central nervous system [450].”
From Guidelines for the use of flow cytometry and cell sorting in immunological studies (third edition) (2021) · cites this paper as [450]
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Cites
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“Remyelination frequently occurs in the context of innate and adaptive immune responses3,4.”
Self-citationOligodendroglia metabolically support axons and contribute to neurodegeneration
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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
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Research works printed but not linked: 1
- Hild, W. Myelinbildung in Kulturen des Zentralnervensystems. Verh. Anat. Ges. 53, 315–317 (1956-1957).
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The blood–brain barrier and blood–tumour barrier in brain tumours and metastases
Arvanitis, C., Ferraro, G. B., & Jain, R. K. (2019) · Nature reviews. Cancer · doi:10.1038/s41568-019-0205-x · Cited by 1,919
Regulatory T Cells and Human Disease
Sakaguchi, S., Mikami, N., Wing, J. B., Tanaka, A., Ichiyama, K., & Ohkura, N. (2020) · Annual Review of Immunology · doi:10.1146/annurev-immunol-042718-041717 · Cited by 1,163
Guidelines for the use of flow cytometry and cell sorting in immunological studies (second edition)
Cossarizza, A., Chang, H., Radbruch, A., Acs, A., Adam, D., Adam‐Klages, S., Agace, W. W., Aghaeepour, N., Akdiş, M., Allez, M., et al. (2019) · European Journal of Immunology · doi:10.1002/eji.201970107 · Cited by 1,007
Regenerating CNS myelin — from mechanisms to experimental medicines
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Self-citationOligodendrocytes in development, myelin generation and beyond
Kuhn, S., Gritti, L., Crooks, D., & Dombrowski, Y. (2019) · Cells · doi:10.3390/cells8111424 · Cited by 625
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Metadata
- Authors
- Dombrowski, Y., O'Hagan, T., Dittmer, M., Penalva, R., Mayoral, S. R., Bankhead, P., Fleville, S., Eleftheriadis, G., Zhao, C., Naughton, M., Hassan, R., Moffat, J., Falconer, J., Boyd, A., Hamilton, P., Allen, I. V., Kissenpfennig, A., Moynagh, P. N., Evergren, E., Perbal, B., Williams, A. C., Ingram, R. J., Chan, J. R., Franklin, R. J. M., & Fitzgerald, D. C.
- Affiliations
- Queen's University Belfast (GB)
- University of California, San Francisco (US)
- Wellcome/MRC Cambridge Stem Cell Institute (GB)
- MRC Centre for Regenerative Medicine (GB)
- Centre National de la Recherche Scientifique (FR)
- Corresponding author
- Fitzgerald, Denise C
- ORCID
- Venue
- Nature Neuroscience
- Published
- 2017-03-13
- Volume
- 20
- Issue
- 5
- Pages
- 674-680
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC5409501
- OpenAlex
- W2595073340
- Cited by
- 533
- References
- 41
- Citations by year
- 2026: 47 · 2025: 60 · 2024: 77 · 2023: 62 · 2022: 60 · 2021: 61 · 2020: 55 · 2019: 57 · 2018: 37 · 2017: 16
- FWCI
- 19.22
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Maynooth University ePrints and eTheses Archive (Maynooth University) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Research Portal (Queen's University Belfast) (submittedVersion, other-oa)
- eScholarship (California Digital Library) (submittedVersion)
- Apollo (University of Cambridge) (submittedVersion)
- Apollo
- Funders
- Memorial Sloan-Kettering Cancer Center
- Wellcome Trust (WT104915MA, 110138/Z/15/Z, 110138, /Z/15/Z, 097922/Z/11/Z)
- Leverhulme Trust (ECF-2014-390)
- Multiple Sclerosis Society
- Rosetrees Trust
- National Institutes of Health
- Directorate for Biological Sciences
- Medical Research Council (MC_PC_12009, MR/K017047/1, WT104915MA)
- Biotechnology and Biological Sciences Research Council (BB/J01026X/1, BB/N003721/1)
- National Institute of General Medical Sciences (K12GM081266)
- National Institute of Neurological Disorders and Stroke (R01NS095889)
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Health Sciences › Medicine › Clinical Neurology › Multiple Sclerosis Research Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Mesenchymal stem cell research
- Keywords
- regulatory T cells, remyelination, oligodendrocyte differentiation, oligodendrocyte precursor cells, CCN3, multiple sclerosis, myelination, central nervous system regeneration
- MeSH terms
- Animals, Brain, Cell Differentiation, Female, Male, Myelin Sheath, Oligodendroglia, Regeneration, Stem Cells, T-Lymphocytes, Regulatory, Mice, Nephroblastoma Overexpressed Protein
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