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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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“Emerging evidence demonstrates that they accumulate in injured tissues and promote wound healing and regeneration of multiple organ systems, including heart muscle (Weirather et al., 2014), skeletal muscle (Burzyn et al., 2013), skin (Ali et al., 2017), and central nervous (Dombrowski et al., 2017).”
BackgroundListon, A., Pasciuto, E., Fitzgerald, D. C., & Yshii, L. (2023) · Nature reviews. Immunology · doi:10.1038/s41577-023-00960-z · Cited by 95
“CCN3 production is important 57 but not essential 61 for this process, with additional molecular mediators potentially including ITGA2 and MCAM influencing oligodendrocyte precursors 62 , and osteopontin working via microglial reprogramming 53 .”
Self-citationReparative T lymphocytes in organ injury
D’Alessio, F. R., Kurzhagen, J. T., & Rabb, H. (2019) · Journal of Clinical Investigation · doi:10.1172/jci124614 · Cited by 91
“CNS Cuprizone-induced demyelination Tregs Promoted oligodendrocyte differentiation and myelin regeneration via CCN3 (137)”
BackgroundShibahara, T., Ago, T., Nakamura, K., Tachibana, M., Yoshikawa, Y., Komori, M., Yamanaka, K., Wakisaka, Y., & Kitazono, T. (2020) · eNeuro · doi:10.1523/eneuro.0474-19.2020 · Cited by 89
Pawlak, M., Ho, A. W., & Kuchroo, V. K. (2020) · Current Opinion in Immunology · doi:10.1016/j.coi.2020.09.001 · Cited by 93
Epigenetic reprogramming of immune cells in injury, repair, and resolution
Placek, K., Schultze, J. L., & Aschenbrenner, A. C. (2019) · Journal of Clinical Investigation · doi:10.1172/jci124619 · Cited by 86
“On the other hand, recent studies show a protective role of T cells in CNS injury (144), acute kidney injury (145), myocardial infarction (146), and muscle repair (137).”
InfluentialDavoli-Ferreira, M., de Lima, K. A., Fonseca, M. M., Guimarães, R. M., Gomes, F. I. F., Cavallini, M. C. M., de Quadros, A. U., Kusuda, R., Cunha, F. Q., Alves-Filho, J. C., et al. (2020) · Pain · doi:10.1097/j.pain.0000000000001879 · Cited by 91
“models of neuronal damage through mechanisms distinct from immunomodulation.(16,29) One important question that emerged from these results was which cell-intrinsic mechanism allowed Treg cells to play an antinociceptive role in our model.”
BackgroundDiet-dependent regulation of TGFβ impairs reparative innate immune responses after demyelination
Bosch-Queralt, M., Cantuti-Castelvetri, L., Damkou, A., Schifferer, M., Schlepckow, K., Alexopoulos, I., Lütjohann, D., Klose, C., Vaculčiaková, L., Masuda, T., et al. (2021) · Nature Metabolism · doi:10.1038/s42255-021-00341-7 · Cited by 88
Brain-resident regulatory T cells and their role in health and disease
Liston, A., Dooley, J., & Yshii, L. (2022) · Immunology Letters · doi:10.1016/j.imlet.2022.06.005 · Cited by 89
Treg cell therapy: How cell heterogeneity can make the difference
Giganti, G., Atif, M., Mohseni, Y., Mastronicola, D., Grageda, N., Povoleri, G. A., Miyara, M., & Scottà, C. (2021) · European Journal of Immunology · doi:10.1002/eji.201948131 · Cited by 82
Duffy, S. S., Keating, B. A., Perera, C. J., Lees, J. G., Tonkin, R. S., Makker, P. G. S., Carrive, P., Butovsky, O., & Moalem‐Taylor, G. (2019) · Journal of Neuroscience · doi:10.1523/jneurosci.1815-18.2019 · Cited by 86
“We then used flow cytometry to look for the presence of GFP Treg cells in central tissues and assess the composition of the CNS inflammatory infiltrate in EAE mice injected with Treg cells compared with EAE mice injected with saline on day 32 after EAE induction.”
BackgroundResultInfluentialImmune‐ and non‐immune‐mediated roles of regulatory T‐cells during wound healing
Zaiss, D. M. W., Minutti, C. M., & Knipper, J. A. (2019) · Immunology · doi:10.1111/imm.13057 · Cited by 84
Microglia: origins, homeostasis, and roles in myelin repair
Lloyd, A. F., Davies, C. L., & Miron, V. E. (2017) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2017.10.001 · Cited by 85
Central Nervous System Remyelination: Roles of Glia and Innate Immune Cells
Baaklini, C. S., Rawji, K. S., Duncan, G. J., Ho, M. F. S., & Plemel, J. R. (2019) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2019.00225 · Cited by 88
Spatial dynamics of brain development and neuroinflammation
Zhang, D., Kirby, L. A., Lin, Y., Wang, W., Song, M., Wang, L., Wang, L., Kanatani, S., Jimenez-Beristain, T., Dang, Y., et al. (2025) · Nature · doi:10.1038/s41586-025-09663-y · Cited by 134
Cross-Talk of the CNS With Immune Cells and Functions in Health and Disease
Matejuk, A., Vandenbark, A. A., & Offner, H. (2021) · Frontiers in Neurology · doi:10.3389/fneur.2021.672455 · Cited by 81
“In this context, oligodendrocyte lineage cells are also responsive to factors produced by regulatory T and B cells that improve remyelination and repair processes (113, 114).”
BackgroundThe Role of Astrocytes in Remyelination
Rawji, K. S., Martinez, G. A. G., Sharma, A., & Franklin, R. J. M. (2020) · Trends in Neurosciences · doi:10.1016/j.tins.2020.05.006 · Cited by 84
Self-citationPu, A., Stephenson, E. L., & Yong, V. W. (2018) · Glia · doi:10.1002/glia.23333 · Cited by 82
“The recent report that Tregs promote remyelination is attributed to their production of the secreted ECM-associated signaling protein nephroblastoma overexpressed (NOV, CCN3; Dombrowski et al., 2017).”
BackgroundTargeting Regulatory T Cells to Treat Patients With Systemic Lupus Erythematosus
Mizui, M., & Tsokos, G. C. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00786 · Cited by 78
“More recently, Tregs were demonstrated to promote directly myelin regeneration in the central nervous system indecently of immunomodulation (49).”
BackgroundTNFR2 promotes Treg-mediated recovery from neuropathic pain across sexes
Fischer, R., Sendetski, M., del Rivero, T., Martinez, G. F., Bracchi-Ricard, V. C., Swanson, K. A., Pruzinsky, E., Delguercio, N., Rosalino, M. J., Padutsch, T., et al. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1902091116 · Cited by 77
“Since both Tregs and TNFR2 on central nervous system (CNS)-resident cells, such as microglia, have been shown to reduce neuroinflammation and to promote neuroprotection (15, 30, 31), we investigated whether EHD2-sc-mTNFR2 was transported into the spinal cord.”
Protective and Regenerative Roles of T Cells in Central Nervous System Disorders
Evans, F., Dittmer, M., de la Fuente, A. G., & Fitzgerald, D. C. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.02171 · Cited by 80
“Treg-conditioned media were also shown to significantly increase myelination and remyelination in ex vivo brain stem slice cultures, and significantly increase oligodendrocyte differentiation in both murine mixed glia and pure OPC culture models (101).”
BackgroundSelf-citationTreg–tissue cell interactions in repair and regeneration
Loffredo, L. F., Savage, T. M., Ringham, O. R., & Arpaia, N. (2024) · The Journal of Experimental Medicine · doi:10.1084/jem.20231244 · Cited by 80
Role of the immune system in regeneration and its dynamic interplay with adult stem cells
Abnave, P., & Ghigo, É. (2018) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2018.04.002 · Cited by 85
Role of Peripheral Immune Cells for Development and Recovery of Chronic Pain
Bethea, J. R., & Fischer, R. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.641588 · Cited by 73
“CNP can result as a consequence of a large number of medical conditions, such as injuries to the PNS or CNS, metabolic, autoimmune or neurodegenerative diseases as well as cancer and chemotherapy (4, 5).”
BackgroundInfluentialCervantes-Llanos, M., Lagumersindez-Denis, N., Marín-Prida, J., Pavón-Fuentes, N., Falcon-Cama, V., Piniella-Matamoros, B., Camacho-Rodríguez, H., Fernández-Massó, J. R., Valenzuela-Silva, C., Raíces-Cruz, I., et al. (2018) · Life Sciences · doi:10.1016/j.lfs.2017.12.032 · Cited by 73
Pentón-Rol, G., Marín-Prida, J., & McCarty, M. F. (2021) · Current Neuropharmacology · doi:10.2174/1570159x19666210408123807 · Cited by 73
“In this line of thinking, another interesting observation related to Treg in MS was reported by Dombrowski et al. (2017).”
Zveik, O., Rechtman, A., Ganz, T., & Vaknin‐Dembinsky, A. (2024) · Molecular Neurodegeneration · doi:10.1186/s13024-024-00742-8 · Cited by 76
“These are further validated by prior research, which has indicated that experimental depletion of macrophages [134], and B or T cells [161, 189] leads to remyelination impairment.”
ResultÁlvarez‐Sánchez, N., Cruz‐Chamorro, I., Díaz‐Sánchez, M., Sarmiento‐Soto, H., Medrano‐Campillo, P., Martínez‐López, A., Lardone, P. J., Guerrero, J. M., & Carrillo‐Vico, A. (2017) · Journal of Pineal Research · doi:10.1111/jpi.12442 · Cited by 64
“In addition to limiting pathogenic responses, Tregs also promote remyelination in vivo.(29) The peripheral frequency of Tregs in MS patients have been found to be unaltered 31 or decreased(32) compared with those in healthy controls, but the cells are functionally impaired, with a decreased proliferative capacity in v…”
BackgroundCrossing boundaries: Interplay between the immune system and oligodendrocyte lineage cells
Kirby, L. A., & Castelo‐Branco, G. (2020) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2020.10.013 · Cited by 66
Regulatory T cells in peripheral tissue tolerance and diseases
Cheru, N. T., Hafler, D. A., & Sumida, T. S. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1154575 · Cited by 67
Promises and limitations of immune cell-based therapies in neurological disorders
Hu, X., Leak, R. K., Thomson, A. W., Yu, F., Xia, Y., Wechsler, L. R., & Chen, J. (2018) · Nature Reviews Neurology · doi:10.1038/s41582-018-0028-5 · Cited by 64
T reg cell–intrinsic requirements for ST2 signaling in health and neuroinflammation
Hemmers, S., Schizas, M., & Rudensky, A. Y. (2020) · The Journal of Experimental Medicine · doi:10.1084/jem.20201234 · Cited by 63
Modeling Immunity In Vitro: Slices, Chips, and Engineered Tissues
Hammel, J. H., Cook, S. R., Belanger, M. C., Munson, J. M., & Pompano, R. R. (2021) · Annual Review of Biomedical Engineering · doi:10.1146/annurev-bioeng-082420-124920 · Cited by 60
“T cell interactions with neurons are also a topic of interest in brain slice studies (144, 145).”
McIntyre, L. L., Greilach, S. A., Othy, S., Sears‐Kraxberger, I., Wi, B., Angulo, J. A. A., Vu, E., Pham, Q., Silva, J., Dang, K., et al. (2020) · Neurobiology of Disease · doi:10.1016/j.nbd.2020.104868 · Cited by 62
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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