Editors' ChoiceImmunology

T Cells Hurt the Brain

Science Signaling  15 Apr 2014:
Vol. 7, Issue 321, pp. ec95
DOI: 10.1126/scisignal.2005368

After an ischemic stroke has occurred, T cells infiltrate the brain. Although T cells have beneficial effects at later time points, during the acute inflammatory response, they cause tissue injury, which makes the search for immunomodulatory therapies a high priority. Clarkson et al. studied inflammatory responses in the brain in mice subjected to transient middle cerebral artery occlusion (tMCAO), a model of ischemic stroke. Microarray analysis showed that the gene encoding the cytokine interleukin-21 (IL-21) was the most highly expressed among inflammation-associated genes in the brain 24 hours after tMCAO, whereas Il21 was not detectable in healthy brain tissue. IL-21 knockout (IL-21 KO) mice exhibited less tissue damage than did wild-type mice 24 hours after tMCAO, and the brains of IL-21 KO mice had fewer infiltrating CD4+ and CD8+ T cells than did the brains of wild-type mice. Flow cytometric analysis of immune cells in the brains of wild-type mice after tMCAO showed that CD4+ T cells were the major source of IL-21. When lymphocyte-deficient mice were subjected to tMCAO, they had less brain tissue damage than did wild-type mice; however, tissue damage was increased in the lymphocyte-deficient mice when they were reconstituted with CD4+ T cells from wild-type mice, but not with those from IL-21 KO mice. Treatment of wild-type mice with an IL-21 receptor blocker early after tMCAO alleviated tissue damage and resulted in improved locomotor function compared to that in control animals. Immunohistochemical staining of postmortem brain tissue from stroke patients detected IL-21+CD4+ T cells in the perivascular spaces. Gene expression analysis showed that the abundance of the transcript encoding the IL-21 receptor was greater in mouse neurons than in other brain cells. Treatment of cultured mouse neuronal cells with IL-21 after oxygen glucose deprivation resulted in increased cell death compared to that in control cells. Together, these data indicate that CD4+ T cell‑derived IL-21 contributes to tissue damage after ischemic stroke, perhaps by inducing neuronal cell death, which suggests that early targeting of IL-21 signaling may provide an effective therapy for stroke patients.

B. D. S. Clarkson, C. Ling, Y. Shi, M. G. Harris, A. Rayasam, D. Sun, M. S. Salamat, V. Kuchroo, J. D. Lambris, M. Sandor, Z. Fabry, T cell–derived interleukin (IL)-21 promotes brain injury following stroke in mice. J. Exp. Med. 211, 595‑604 (2014). [Abstract] [Full Text]