Pivotal role of cerebral interleukin-17–producing γδT cells in the delayed phase of ischemic brain injury

T Shichita, Y Sugiyama, H Ooboshi, H Sugimori… - Nature medicine, 2009 - nature.com
T Shichita, Y Sugiyama, H Ooboshi, H Sugimori, R Nakagawa, I Takada, T Iwaki, Y Okada…
Nature medicine, 2009nature.com
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 …
Abstract
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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