Letter abstract

Nature Medicine 15, 946 - 950 (2009)
Published online: 2 August 2009 | doi:10.1038/nm.1999

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

Takashi Shichita1,2,3, Yuki Sugiyama1, Hiroaki Ooboshi3,4, Hiroshi Sugimori3, Ryusuke Nakagawa1, Ichiro Takada1, Toru Iwaki5, Yasunori Okada6, Mitsuo Iida3, Daniel J Cua7, Yoichiro Iwakura8 & Akihiko Yoshimura1,9


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.

  1. Department of Microbiology and Immunology, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan.
  2. Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
  3. Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
  4. Department of Internal Medicine, Fukuoka Dental College Medical and Dental Hospital, Fukuoka, Japan.
  5. Department of Neuropathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
  6. Department of Pathology, School of Medicine, Keio University, Shijuku-ku, Tokyo, Japan.
  7. Department of Immunology, Schering-Plough, Palo Alto, California, USA.
  8. Center for Experimental Medicine and Department of Cancer Biology, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
  9. Japan Science and Technology Agency, Core Research for Evolutional Science and Technology (CREST), Tokyo, Japan.

Correspondence to: Akihiko Yoshimura1,9 e-mail: yoshimura@a6.keio.jp