1. Treg cell-derived osteopontin promotes microglia-mediated white matter repair after ischemic stroke
- Author
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Qingxiu Zhang, Di Xie, Ligen Shi, Donna B. Stolz, Xuejiao Dai, Kong Chen, Lesley M. Foley, Kartik Iyer, Jun Chen, T. Kevin Hitchens, Xiaoming Hu, Rehana K. Leak, Zeyu Sun, Sicheng Li, Wei Su, Ying Ding, Fei Xu, and Angus W. Thomson
- Subjects
0301 basic medicine ,Male ,Immunology ,chemical and pharmacologic phenomena ,T-Lymphocytes, Regulatory ,Flow cytometry ,Brain Ischemia ,Transcriptome ,White matter ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Immune system ,medicine ,Immunology and Allergy ,Animals ,Osteopontin ,Ischemic Stroke ,biology ,Microglia ,medicine.diagnostic_test ,Regeneration (biology) ,Macrophages ,hemic and immune systems ,Recovery of Function ,White Matter ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,Infectious Diseases ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,biology.protein ,Cancer research ,Interleukin-2 ,Antibody - Abstract
Summary The precise mechanisms underlying the beneficial effects of regulatory T (Treg) cells on long-term tissue repair remain elusive. Here, using single-cell RNA sequencing and flow cytometry, we found that Treg cells infiltrated the brain 1 to 5 weeks after experimental stroke in mice. Selective depletion of Treg cells diminished oligodendrogenesis, white matter repair, and functional recovery after stroke. Transcriptomic analyses revealed potent immunomodulatory effects of brain-infiltrating Treg cells on other immune cells, including monocyte-lineage cells. Microglia depletion, but not T cell lymphopenia, mitigated the beneficial effects of transferred Treg cells on white matter regeneration. Mechanistically, Treg cell-derived osteopontin acted through integrin receptors on microglia to enhance microglial reparative activity, consequently promoting oligodendrogenesis and white matter repair. Increasing Treg cell numbers by delivering IL-2:IL-2 antibody complexes after stroke improved white matter integrity and rescued neurological functions over the long term. These findings reveal Treg cells as a neurorestorative target for stroke recovery.
- Published
- 2020