Pivotal role of cerebral interleukin-17-producing gammadeltaT cells in the delayed phase of ischemic brain injury.
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 gammadeltaT lymphocytes, but not CD4(+) helper T cells, were a major source of IL-17. Moreover, depletion of gammadeltaT lymphocytes ameliorated the I/R injury. We propose that T lymphocytes, including gammadeltaT lymphocytes, could be a therapeutic target for mitigating the inflammatory events that amplify the initial damage in cerebral ischemia.
Shichita
Takashi
T
Department of Microbiology and Immunology, School of Medicine, Keio University, Tokyo, Japan.
Sugiyama
Yuki
Y
Ooboshi
Hiroaki
H
Sugimori
Hiroshi
H
Nakagawa
Ryusuke
R
Takada
Ichiro
I
Iwaki
Toru
T
Okada
Yasunori
Y
Iida
Mitsuo
M
Cua
Daniel J
DJ
Iwakura
Yoichiro
Y
Yoshimura
Akihiko
A
D000818:Animals; D001930:Brain Injuries / Q000209:etiology / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D002545:Brain Ischemia / Q000150:complications / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics; D007371:Interferon-gamma / Q000235:genetics; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism*; D053760:Interleukin-23 Subunit p19 / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000235:genetics / Q000378:metabolism*; D015427:Reperfusion Injury / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism / Q000502:physiology*; D013997:Time Factors
D004268:DNA-Binding Proteins; D020381:Interleukin-17; D053760:Interleukin-23 Subunit p19; C499308:Rag2 protein, mouse; D016692:Receptors, Antigen, T-Cell, gamma-delta; D007371:Interferon-gamma