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

Nature Medicine volume 15, pages 946–950 (2009)Cite this article

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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Figure 1: Effect of inflammatory cytokines on ischemic brain damage.
Figure 2: Infiltration of macrophages and T cells into the ischemic brain and their roles in inflammation.
Figure 3: Major producer cells of IL-23 and IL-17 in the ischemic brain.
Figure 4: The effects of γδT lymphocyte depletion in ischemic brain tissue.

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Acknowledgements

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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Authors and Affiliations

  1. Department of Microbiology and Immunology, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan

    Takashi Shichita, Yuki Sugiyama, Ryusuke Nakagawa, Ichiro Takada & Akihiko Yoshimura

  2. Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan

    Takashi Shichita

  3. Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    Takashi Shichita, Hiroaki Ooboshi, Hiroshi Sugimori & Mitsuo Iida

  4. Department of Internal Medicine, Fukuoka Dental College Medical and Dental Hospital, Fukuoka, Japan

    Hiroaki Ooboshi

  5. Department of Neuropathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    Toru Iwaki

  6. Department of Pathology, School of Medicine, Keio University, Shijuku-ku, Tokyo, Japan

    Yasunori Okada

  7. Department of Immunology, Schering-Plough, Palo Alto, California, USA

    Daniel J Cua

  8. Center for Experimental Medicine and Department of Cancer Biology, Institute of Medical Science, University of Tokyo, Tokyo, Japan

    Yoichiro Iwakura

  9. Japan Science and Technology Agency, Core Research for Evolutional Science and Technology (CREST), Tokyo, Japan

    Akihiko Yoshimura

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  1. Takashi Shichita
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Contributions

T.S. designed and performed experiments, analyzed data and wrote the manuscript; Y.S. performed experiments and analyzed data; H.O. contributed to the experimental design, analysis and manuscript writing; H.S. performed experiments; R.N. provided specific input into flow cytometry and mouse analysis, I.T. contributed to manuscript writing; T.I. and Y.O. contributed to histochemistry; M.I. contributed to the experimental design; D.J.C. and Y.I. provided mice and critical input on IL-23 and IL-17 functions; A.Y. initiated and directed the entire study, designed experiments and wrote the manuscript.

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Correspondence to Akihiko Yoshimura.

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Supplementary Figs. 1–7, Supplementary Tables 1–4 and Supplementary Methods (PDF 564 kb)

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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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