Neuroprotection against ischemic stroke requires a specific class of early responder T cells in mice
Wei Cai, … , Xiaoming Hu, Jun Chen
Wei Cai, … , Xiaoming Hu, Jun Chen
Published August 1, 2022
Citation Information: J Clin Invest. 2022;132(15):e157678. https://doi.org/10.1172/JCI157678.
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Research Article Inflammation Neuroscience

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

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.

Authors

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

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Figure 6

LIFR mediates the beneficial effects of CD8+ TRLs after stroke.

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LIFR mediates the beneficial effects of CD8+ TRLs after stroke. (A) Tran...
(A) Transwell coculture system of brain slices collected 1 day after stroke and CD8+ TRLs from healthy spleens. RT-PCR analysis of Lifr, Tgfa, and Il10 24 hours after coculture. Kruskal-Wallis test and post hoc Dunn’s test. n = 6–16/group. (B) Anti-LIF antibody (60 ng/mL) was added to the CD8+ TRL–brain slice coculture system (as in A). The expression of Tgfa and Il10 was measured by RT-PCR 24 hours after coculture. n = 4–6/group. One-way ANOVA and post hoc Bonferroni’s test. CL, contralateral brain; IP, ipsilateral brain. (C–G) Spleen-derived CD8+ TRLs were pretreated with LIF (100 ng/mL), LIFR inhibitor (EC359, 100 nM), or PBS for 1 hour and then injected (i.v., 1 × 106 cells) into recipient mice 2 hours after tMCAO. (D and E) LIF treatment enhanced ETGF and IL-10 expression in CD8+ TRLs. n = 3/group. Two-tailed Student’s t test. (F) Quantification of MAP2 staining and (G) Garcia score. n = 5–6/group. One-way ANOVA and post hoc Bonferroni’s test. *P < 0.05; **P < 0.01; ***P < 0.001.