The Journal of Clinical Investigation (Aug 2022)

Neuroprotection against ischemic stroke requires a specific class of early responder T cells in mice

  • Wei Cai,
  • Ligen Shi,
  • Jingyan Zhao,
  • Fei Xu,
  • Connor Dufort,
  • Qing Ye,
  • Tuo Yang,
  • Xuejiao Dai,
  • Junxuan Lyu,
  • Chenghao Jin,
  • Hongjian Pu,
  • Fang Yu,
  • Sulaiman Hassan,
  • Zeyu Sun,
  • Wenting Zhang,
  • T. Kevin Hitchens,
  • Yejie Shi,
  • Angus W. Thomson,
  • Rehana K. Leak,
  • Xiaoming Hu,
  • Jun Chen

Journal volume & issue
Vol. 132, no. 15

Abstract

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Immunomodulation holds therapeutic promise against brain injuries, but leveraging this approach requires a precise understanding of mechanisms. We report that CD8+CD122+CD49dlo T regulatory-like cells (CD8+ TRLs) are among the earliest lymphocytes to infiltrate mouse brains after ischemic stroke and temper inflammation; they also confer neuroprotection. TRL depletion worsened stroke outcomes, an effect reversed by CD8+ TRL reconstitution. The CXCR3/CXCL10 axis served as the brain-homing mechanism for CD8+ TRLs. Upon brain entry, CD8+ TRLs were reprogrammed to upregulate leukemia inhibitory factor (LIF) receptor, epidermal growth factor–like transforming growth factor (ETGF), and interleukin 10 (IL-10). LIF/LIF receptor interactions induced ETGF and IL-10 production in CD8+ TRLs. While IL-10 induction was important for the antiinflammatory effects of CD8+ TRLs, ETGF provided direct neuroprotection. Poststroke intravenous transfer of CD8+ TRLs reduced infarction, promoting long-term neurological recovery in young males or aged mice of both sexes. Thus, these unique CD8+ TRLs serve as early responders to rally defenses against stroke, offering fresh perspectives for clinical translation.

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