In addition to maintaining immune tolerance, FOXP3+ regulatory T (Treg) cells perform specialized functions in tissue homeostasis and remodelling1,2. However, the characteristics and functions of brain Treg cells are not well understood because there is a low number of Treg cells in the brain under normal conditions. Here we show that there is massive accumulation of Treg cells in the mouse brain after ischaemic stroke, and this potentiates neurological recovery during the chronic phase of ischaemic brain injury. Although brain Treg cells are similar to Treg cells in other tissues such as visceral adipose tissue and muscle3,4,5, they are apparently distinct and express unique genes related to the nervous system including Htr7, which encodes the serotonin receptor 5-HT7. The amplification of brain Treg cells is dependent on interleukin (IL)-2, IL-33, serotonin and T cell receptor recognition, and infiltration into the brain is driven by the chemokines CCL1 and CCL20. Brain Treg cells suppress neurotoxic astrogliosis by producing amphiregulin, a low-affinity epidermal growth factor receptor (EGFR) ligand. Stroke is a leading cause of neurological disability, and there are currently few effective recovery methods other than rehabilitation during the chronic phase. Our findings suggest that Treg cells and their products may provide therapeutic opportunities for neuronal protection against stroke and neuroinflammatory diseases.
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The microarray data for brain Treg cells are available in the Gene Expression Omnibus (GEO) database under accession number GSE109259. Source Data for figures are provided with the paper.
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We thank K. Sawamoto and K. Tanaka for comments, N. Shiino, C. Ohkura, Y. Tokifuji and Y. Hirata for technical assistance, and T. Srirat for checking the English. This work was supported by JSPS KAKENHI (S) JP17H06175, Challenging Research (P) JP18H05376, and AMED-CREST JP18gm0510019 and JP18gm1110009 to A.Y., AMED-PRIME JP18gm5910023, and AMED JP18ek0210100 to T.S., the Takeda Science Foundation, the Uehara Memorial Foundation, the Kanae Foundation, and the SENSHIN Medical Research Foundation, and Keio Gijuku Academic Developmental Funds. M.I. and M.I.-K. were supported by JSPS post-doctoral fellowship.
Nature thanks S. Liddelow, T. Masuda, M. Prinz, A. Rudensky and the anonymous reviewer(s) for their contribution to the peer review of this work.
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Seminars in Immunopathology (2019)