Treg cell-derived osteopontin promotes microglia-mediated white matter repair after ischemic stroke
microglia, oligodendrocytes, osteopontin, regulatory T cells, stroke recovery, white matter
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.
Shi, L., Sun, Z., Su, W., Xu, F., Xie, D., Zhang, Q., Dai, X., Iyer, K., Hitchens, T. K., Foley, L. M., Li, S., Stolz, D. B., Chen, K., Ding, Y., Thomson, A. W., Leak, R. K., Chen, J., & Hu, X. (2021). Treg cell-derived osteopontin promotes microglia-mediated white matter repair after ischemic stroke. Immunity, 54 (7), 1527-1.54E+11. https://doi.org/10.1016/j.immuni.2021.04.022