Neuroprotection against ischemic stroke requires a specific class of early responder T cells in mice
Journal of Clinical Investigation
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.
Cai, W., Shi, L., Zhao, J., Xu, F., Dufort, C., Ye, Q., Yang, T., Dai, X., Lyu, J., Jin, C., Pu, H., Yu, F., Hassan, S., Sun, Z., Zhang, W., Kevin Hitchens, T., Shi, Y., Thomson, A., Leak, R., Hu, X., & Chen, J. (2022). Neuroprotection against ischemic stroke requires a specific class of early responder T cells in mice. Journal of Clinical Investigation, 132 (15). https://doi.org/10.1172/JCI157678