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Cited by 52Multiple Sclerosis Research StudiesT-cell and B-cell ImmunologyPeripheral Neuropathies and Disorders

Regulatory T cells protect against brain damage by alleviating inflammatory response in neuromyelitis optica spectrum disorder

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Ma, Xue, Qin, Chuan, Chen, Man, Yu, Hai-Han, Chu, Yun-Hui, Chen, Ting-Jun, Bosco, Dale B., Wu, Long-Jun +3 more·2021·Journal of Neuroinflammation
DOI 10.1186/s12974-021-02266-0PMC PMC8444427
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Abstract

Background and purpose: Neuromyelitis optica spectrum disorder (NMOSD) is mainly an anti-aquaporin 4 (anti-AQP4) autoantibodies-mediated idiopathic inflammatory demyelinating disease of the central nervous system. Systemic and local inflammatory responses play a key role in the pathophysiology of NMOSD. However, the role of the crucial immunomodulators CD4 + CD25 + forkhead box P3 + (Foxp3) regulatory T cells (Tregs) has not been investigated in NMOSD. Methods: Twenty-five patients with anti-AQP4-postive NMOSD undergoing an attack and 21 healthy controls (HCs) were enrolled. Frequencies of T cell subsets and Tregs in the peripheral blood were assessed by flow cytometry. Additionally, a model of NMOSD using purified immunoglobulin G from anti-AQP4-antibodies-positive patients with NMOSD and human complement injected into brain of female adult C57BL/6J mice was established. Infiltrated Tregs into NMOSD mouse brain lesions were analyzed by flow cytometry, histological sections, and real-time quantitative Polymerase Chain Reaction. Astrocyte loss, demyelination, and inflammatory response were also evaluated in our NMOSD mouse model. Finally, we examined the effects of both depletion and adoptive transfer of Tregs. Results: The percentage of Tregs, especially naïve Tregs, among total T cells in peripheral blood was significantly decreased in NMOSD patients at acute stage when compared to HCs. Within our animal model, the number and proportion of Tregs among CD4 + T cells were increased in the lesion of mice with NMOSD. Depletion of Tregs profoundly enhanced astrocyte loss and demyelination in these mice, while adoptive transfer of Tregs attenuated brain damage. Mechanistically, the absence of Tregs induced more macrophage infiltration, microglial activation, and T cells invasion, and modulated macrophages/microglia toward a classical activation phenotype, releasing more chemokines and pro-inflammatory cytokines. In contrast, Tregs transfer ameliorated immune cell infiltration in NMOSD mice, including macrophages, neutrophils, and T cells, and skewed macrophages and microglia towards an alternative activation phenotype, thereby decreasing the level of chemokines and pro-inflammatory cytokines. Conclusion: Tregs may be key immunomodulators ameliorating brain damage via dampening inflammatory response after NMOSD.

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  • FOXP3+ AQP4-specific ThEx cells are not derived from an unstable thymic Treg precursor.

    “indicating that they are not derived from an unstable thymic Treg precursor, as described in various AIDs 71,72 including NMOSD. 73-76”

    From Autoantigen-specific CD4+ T cells acquire an exhausted phenotype and persist in human antigen-specific autoimmune diseases (2024) · cites this paper as [74]

    The Discussion (page unavailable) distinguishes thymus-derived naïve Tregs from peripheral effector Tregs and reports fewer naïve Tregs in acute NMOSD. The Results examine Treg depletion and transfer, but neither section addresses whether FOXP3+ AQP4-specific ThEx cells arise from an unstable thymic Treg precursor. Searches for that cell population and its lineage found no decisive passage. (LLM, conf=0.75)

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Authors
Ma, X., Qin, C., Chen, M., Yu, H.-H., Chu, Y.-H., Chen, T.-J., Bosco, D. B., Wu, L.-J., Bu, B.-T., Wang, W., & Tian, D.-S.
Affiliations
  • Tongji Hospital (CN)
  • Mayo Clinic (US)
Corresponding author
  • Wang, Wei
  • Tian, Dai-Shi
ORCID
Venue
Journal of Neuroinflammation
Publisher
Springer Science and Business Media LLC
Published
2021-09-15
Volume
18
Issue
1
Pages
201-201
ISSN
1742-2094 (ISSN-L)
DOI
10.1186/s12974-021-02266-0
PMC
PMC8444427
OpenAlex
W3201545960
Cited by
52
References
55
Citations by year
2026: 10 · 2025: 12 · 2024: 12 · 2023: 10 · 2022: 7 · 2021: 1
FWCI
5.00
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Neuroinflammation (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Natural Science Foundation of China (82071380, 81873743, 81801223)
  • Tongji Hospital (HUST) Foundation for Excellent Young Scientist (2020YQ06)
Topics
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
  • Health Sciences › Medicine › Neurology › Peripheral Neuropathies and Disorders
Keywords
neuromyelitis optica spectrum disorder, regulatory T cells, Foxp3, demyelination, astrocyte loss, neuroinflammation, macrophage polarization, microglial activation, adoptive Treg transfer, Treg depletion, brain lesions, chemokines, inflammatory cytokines, immunomodulation
MeSH terms
Animals, Autoantibodies, Brain, Female, Humans, Mice, Inbred C57BL, Neuromyelitis Optica, T-Lymphocytes, Regulatory, Mice, Aquaporin 4

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