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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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Lou, Z., Post, A., Nagoshi, N., Hong, J., Hejrati, N., Chio, J. C. T., Khazaei, M., & Fehlings, M. G. (2024) · Stem Cells Translational Medicine · doi:10.1093/stcltm/szae090 · Cited by 5
The Roles of Regulatory T Cells in Central Nervous System Autoimmunity
Keating, B. A., Lees, J. G., & Moalem‐Taylor, G. (2019) · Contemporary clinical neuroscience · doi:10.1007/978-3-030-19515-1_6 · Cited by 3
Thomé, R., Boehm, A., Ishikawa, L. L. W., Casella, G., Munhoz, J., Ćirić, B., Zhang, G., & Rostami, A. M. (2020) · Brain Sciences · doi:10.3390/brainsci10060348 · Cited by 3
“Additionally, Treg cells were shown to promote remyelination [11,12].”
BackgroundAdonias, G. L., Duffy, C. P., Barros, M. T., McCoy, C. E., & Balasubramaniam, S. (2021) · IEEE Transactions on Neural Systems and Rehabilitation Engineering · doi:10.1109/tnsre.2021.3137350 · Cited by 3
“LPC-induced demyelination was observed to be of a similar magnitude in our hands as reported by several other groups [13], [14], [30].”
ResultElevated reactive aggression in forebrain‐specific Ccn2 knockout mice
Chang, H., Ng, C., Chen, Y., Wang, Y., Yu, I., Lee, L. J., Lee, L., & Lee, K. (2024) · Journal of Cell Communication and Signaling · doi:10.1002/ccs3.12040 · Cited by 3
“63 In our Fb Ccn2 − / − mice, increased mature oligo-dendrocytes are noticed in the external capsule, 13 supporting the suppressive effect of CCN2 on oligodendrocytes.”
BackgroundMini-Review: Tregs as a Tool for Therapy—Obvious and Non-Obvious Challenges and Solutions
Morgun, E. I., Govorova, I. A., Chernysheva, M. B., Machinskaya, M. A., & Vorotelyak, E. A. (2024) · Cells · doi:10.3390/cells13201680 · Cited by 3
“In vivo experiments on Treg-depleted mice on a model of multiple sclerosis demonstrated that Treg cells play a pivotal role in remyelination of nerve fiber and oligodendrocyte differentiation through the production of CCN3, a multifunctional factor involved in regeneration [10,11].”
Treg Upregulation by Treadmill Training Accelerates Myelin Repair Post-Ischemia
Zhong, J., Liu, T., He, Y., Zhu, Y., Li, S., Liu, Y., Yang, C., Yu, L., Pan, L., Yin, Y., et al. (2025) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-025-10178-6 · Cited by 3
“In multiple sclerosis (MS) models, trophic factors released by Treg cells (Tregs) directly promote the differentiation and maturation of oligodendrocytes (OLs) (Dombrowski, O’Hagan et al. 2017).”
Calderazzo, S., Tavel, D., Zurich, M., & Kopp‐Schneider, A. (2019) · Archives of Toxicology · doi:10.1007/s00204-019-02520-8 · Cited by 3
Regulatory T-cells are required for neonatal heart regenerationPreprint
Li, J., Yang, Y., Tam, R. C. Y., Chan, V. W., Sheng, B., Hori, S., Zhou, B., Lo, Y. M. D., & Lui, K. O. (2018) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/355065 · Cited by 3
de la Fuente, A. G., Dittmer, M., Heesbeen, E. J., Gallardo, N. D. L. V., White, J. A., Young, A., McColgan, T., Dashwood, A., Mayne, K., Cabeza‐Fernández, S., et al. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.01.25.525562 · Cited by 3
Self-citationInflammatory Demyelinating Diseases of the Central Nervous System
Li, M., & Liu, Q. (2024) · Advances in neurobiology · doi:10.1007/978-3-031-69188-1_8 · Cited by 3
He, J., Meng, Q., Miao, C., Hao, J., & Dai, M. (2024) · Postgraduate Medical Journal · doi:10.1093/postmj/qgae125 · Cited by 2
RetractedCD4+CD25+ regulatory T cell therapy in neurological autoimmune diseases
Yuan, G., Liu, Y., Wang, H., Yang, T., & Liu, G.-Z. (2025) · PeerJ · doi:10.7717/peerj.19450 · Cited by 3
“Tregs act on oligodendrocyte progenitor cells (OPCs) by secreting cellular communication network-3 (CCN3) protein, accelerating their differentiation into oligodendrocytes, and promoting myelination ( Dombrowski et al., 2017 ).”
Orhan, M. D., Oktay, L., Cınar, A. I., Yesil, A. K., Tunç, H., Eren, F., Durdağı, S., & Avsar, T. (2025) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.5c00519 · Cited by 2
Chen, Z., Wang, Q., Xiang, R., Ding, R., Tao, J., Peng, Q., Wang, S., Cheng, N., Zhao, M., Li, J., et al. (2025) · Clinical and Translational Medicine · doi:10.1002/ctm2.70486 · Cited by 2
Dong, S., Zhang, T., Zhai, Y., Naatz, L. C., Carlson, N. G., ROSE, J. W., Evavold, B. D., & Chen, M. (2025) · iScience · doi:10.1016/j.isci.2025.113677 · Cited by 2
“…factor CCN3 Tregs have been shown to promote myelin regeneration in the CNS, a process critical for recovery in autoimmune diseases such as MS. 41,43,44 Following the validation of the ‘‘3-in-One’’ function of PD-1 CAR Tregs, we assessed their potential role in stimulating remyelination by…”
Wu, J., Liu, K., Song, J.-Q., Huang, L., Gao, J., Li, F., & Pang, T. (2025) · Archives of Pharmacal Research · doi:10.1007/s12272-025-01576-8 · Cited by 2
“Recent studies underscore that T reg cells facilitate immune homeostasis not only through interactions with various immune cell types, but also by creating an anti-inflammatory environment via cytokine release (e.g., IL-10 and TGF-β) (Collison et al. 2007; Dombrowski et al. 2017).”
Osmond, G. E., John, N. A., Ting, Y. T., & Ooi, J. D. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms262311534 · Cited by 2
“Tregs have been found to promote oligodendrocyte differentiation and remyelination by expression of CCN3 [117], polarise local macrophages/microglia toward an anti-inflammatory pro-healing phenotype by releasing IL-10 [118], and secrete amphiregulin to limit astrogliosis (pathological…”
Immunomodulatory biomaterials for vascularized and innervated skeletal muscle repair
Mottel, L. G., Shields, B. R., & Kwee, B. J. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1657015 · Cited by 3
Neuroglia in traumatic brain injury: Pathophysiology and therapeutic targeting
Suk, K. (2026) · Brain Network Disorders · doi:10.1016/j.bnd.2026.03.002 · Cited by 2
Fu, H., Yang, J., & Zhang, M. Y. (2026) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2026.1838306 · Cited by 2
“Tregs also participate in tissue repair following injury, sustaining tissue homeostasis by suppressing inflammation and facilitating tissue regeneration (Dombrowski et al., 2017).”
Sonic Hedgehog Is an Early Oligodendrocyte Marker During Remyelination
Russo, M., Zahaf, A., Kassoussi, A., Sharif, A., Faure, H., Traiffort, É., & Ruat, M. (2024) · Cells · doi:10.3390/cells13211808 · Cited by 2
Selected Aspects of the Neuroimmunology of Cell Therapies for Neurologic Disease
Ransohoff, R. M. (2024) · Neurology Neuroimmunology & Neuroinflammation · doi:10.1212/nxi.0000000000200352 · Cited by 2
Modulation of proteoglycan receptor regulates RhoA/CRMP2 pathways and promotes axonal myelination
Yao, M., Fang, J., Tao, W., Feng, G., Wei, M., Gao, Y., Xin, W., Li, Y., & Du, S. (2021) · Neuroscience Letters · doi:10.1016/j.neulet.2021.136079 · Cited by 2
T Cells and Their Subsets in Autoimmunity
Burkett, P. R., Pawlak, M., Peters, A., & Kuchroo, V. K. (2019) · Elsevier eBooks · doi:10.1016/b978-0-12-812102-3.00006-3 · Cited by 2
Ischemic Brain Injury and Regulatory T Cells
Ito, M., Srirat, T., Nakamura, T., Komai, K., & Yoshimura, A. (2019) · OBM Neurobiology · doi:10.21926/obm.neurobiol.1901023 · Cited by 2
Calvo‐Barreiro, L., Clerico, M., & Espejo, C. (2021) · Multiple Sclerosis Journal · doi:10.1177/13524585211016723 · Cited by 2
Su, T., Lang, Y., Ren, J., Yin, X., Zhang, W., & Cui, L. (2024) · Molecular Neurobiology · doi:10.1007/s12035-024-04376-1 · Cited by 2
“For example, SCFAs can indirectly promote myelin regeneration and oligodendrocyte differentiation by increasing the number of regulatory T cells [47].”
Gisevius, B., Haghikia, A., & Hirschberg, S. (2019) · e-Neuroforum · doi:10.1515/nf-2018-0013 · Cited by 2
“In addition to the vaginal passage (Dominguez-Bello et al., 2010), another factor known to contribute to the origin of gut microbiota, is breast-feeding (Backhed et al., 2015).”
BackgroundWang, Y., Zhao, Y., Ye, M., Wang, L., Lan, T., Wang, Y., & Qi, Z. (2021) · Research Square · doi:10.21203/rs.3.rs-1007673/v1 · Cited by 2
Enkephalin-mediated modulation of basal somatic sensitivity by regulatory T cells in micePreprint
Aubert, N., Purcarea, M., Fornier, M., Cagnet, L., Naturel, M., Casrouge, A., Dietrich, G., Dieu‐Nosjean, M., & Marodon, G. (2024) · eLife · doi:10.7554/elife.91359.1 · Cited by 2
Ellul, P., Fourcade, G., Mhanna, V., Coatnoan, N., Bodula, S., Seilhean, D., Mouton, L., Marguerit, G., Delorme, R., Tian, M., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.01.06.631430 · Cited by 3
Neuroprotection induced by apigenin
dos Santos, C. C., Carreira, R. B., Dourado, N. S., de Araújo, F. M., de Almeida, M. M. A., de Souza, V. M., Soares, J. R. P., do Nascimento, R. P., de Oliveira, J. V. R., Victor, M. M., et al. (2024) · Elsevier eBooks · doi:10.1016/b978-0-443-23763-8.00025-7 · Cited by 2
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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