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

  • J Clin Invest. 2022 Aug 1;132(15):e157678. doi: 10.1172/JCI157678.
Wei Cai  1 ,  Ligen Shi  1 ,  Jingyan Zhao  1 ,  Fei Xu  1  2 ,  Connor Dufort  1 ,  Qing Ye  1  2 ,  Tuo Yang  1  2 ,  Xuejiao Dai  1 ,  Junxuan Lyu  1 ,  Chenghao Jin  1 ,  Hongjian Pu  1  2 ,  Fang Yu  1 ,  Sulaiman Hassan  1  2 ,  Zeyu Sun  1 ,  Wenting Zhang  1  2 ,  T Kevin Hitchens  3 ,  Yejie Shi  1  2 ,  Angus W Thomson  4 ,  Rehana K Leak  5 ,  Xiaoming Hu  1  2 ,  Jun Chen  1  2
Affiliations
  • 1. Pittsburgh Institute of Brain Disorders and Recovery, and Department of Neurology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
  • 2. Geriatric Research, Education and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, Pennsylvania, USA.
  • 3. Animal Imaging Center and Department of Neurobiology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
  • 4. Starzl Transplantation Institute, Department of Surgery, and Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
  • 5. Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, Pennsylvania, USA.
PMID: 35912857 DOI: 10.1172/JCI157678
Abstract

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.

Keywords
Immunotherapy; Inflammation; Neuroscience; Stroke; T cells.
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