Lymphocyte recruitment and activation have been implicated in the progression of cerebral ischemia-reperfusion (I/R) injury, but the roles of specific lymphocyte subpopulations and cytokines during stroke remain to be clarified. Here we demonstrate that the infiltration of T cells into the brain, as well as the cytokines interleukin-23 (IL-23) and IL-17, have pivotal roles in the evolution of brain infarction and accompanying neurological deficits. Blockade of T cell infiltration into the brain by the immunosuppressant FTY720 reduced I/R-induced brain damage. The expression of IL-23, which was derived mostly from infiltrated macrophages, increased on day 1 after I/R, whereas IL-17 levels were elevated after day 3, and this induction of IL-17 was dependent on IL-23. These data, together with analysis of mice genetically disrupted for IL-17 and IL-23, suggest that IL-23 functions in the immediate stage of I/R brain injury, whereas IL-17 has an important role in the delayed phase of I/R injury during which apoptotic neuronal death occurs in the penumbra. Intracellular cytokine staining revealed that γδT lymphocytes, but not CD4+ helper T cells, were a major source of IL-17. Moreover, depletion of γδT lymphocytes ameliorated the I/R injury. We propose that T lymphocytes, including γδT lymphocytes, could be a therapeutic target for mitigating the inflammatory events that amplify the initial damage in cerebral ischemia.
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We thank S. Hamano for TCRγδ-specific antibody hybridoma, T. Yoshioka, N. Shiino and M. Asakawa for technical assistance, E. Ishikawa and H. Noguchi for technical support for human ischemic brain section, T. Kobayashi for discussion and technical help and N. Soma for manuscript preparation. This study was supported by special Grants-in-Aid from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, the Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation (NIBIO, 07-4), the Naito Foundation and the Astellas Foundation for Research on Metabolic Disorders.
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Shichita, T., Sugiyama, Y., Ooboshi, H. et al. Pivotal role of cerebral interleukin-17–producing γδT cells in the delayed phase of ischemic brain injury. Nat Med 15, 946–950 (2009). https://doi.org/10.1038/nm.1999
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