Jianan Lu, Qia Zhang, Jiarui Chen, Huaming Li, An Ping, Ziyang Jin, Xiaotao Zhang, Yichen Gu, Xuejiao Dai, Zihong Chen, Yajun Qian, Guoqiang Zhang, Jun Yu, Jianmin Zhang, Ligen Shi
The neutrophil-to-lymphocyte ratio (NLR) is associated with unfavorable prognosis and hemorrhagic transformation (HT) in patients with ischemic stroke, yet the underlying mechanisms remain unclear. Using patient samples and a murine stroke model, we identified CD8⁺ regulatory T cells (CD8 Tregs) key regulators of neutrophil homeostasis after ischemic stroke, thereby limiting endothelial disruption and HT. Loss of CD8 Tregs expanded circulating neutrophils by extending their lifespan rather than altering proliferation, bone marrow release, or direct cytotoxicity. Mechanistically, CD8 Tregs shortened neutrophil lifespan by modulating HIF-1α-dependent glycolytic activity and relieving PD-L1-mediated suppression of bone marrow clearance. Finally, co-culture experiments with human CD8 Tregs and neutrophils revealed similar neutrophil-regulatory effects, accompanied by improved endothelial barrier integrity. These findings reveal a previously unrecognized CD8 Treg-neutrophil axis and suggest potential therapeutic strategies for preventing HT after stroke.