Neuroprotection against ischemic stroke requires a specific class of early responder T cells in mice.
Neuroprotection against ischemic stroke requires a specific class of early responder T cells in mice.
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DOI：
10.1172/jci157678
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发表时间：
2022-08-01
影响因子：
15.9
通讯作者：
Chen, Jun
中科院分区：
文献类型：
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作者：
Cai, Wei;Shi, Ligen;Zhao, Jingyan;Xu, Fei;Dufort, Connor;Ye, Qing;Yang, Tuo;Dai, Xuejiao;Lyu, Junxuan;Jin, Chenghao;Pu, Hongjian;Yu, Fang;Hassan, Sulaiman;Sun, Zeyu;Zhang, Wenting;Hitchens, T. Kevin;Shi, Yejie;Thomson, Angus W.;Leak, Rehana K.;Hu, Xiaoming;Chen, Jun
免疫调节具有治疗脑损伤的前景，但利用这种方法需要对机制的精确理解。我们报道了CD 8 + CD 122 + CD 49 dlo T调节样细胞（CD 8 + TRLs）是缺血性中风后最早浸润小鼠大脑的淋巴细胞之一，并可缓解炎症;它们还具有神经保护作用。TRL耗竭使卒中结局恶化，CD 8 + TRL重建可逆转该效应。CXCR 3/CXCL 10轴作为CD 8 + TRLs的脑归巢机制。进入脑后，CD 8 + TRL被重编程以上调白血病抑制因子（LIF）受体、表皮生长因子样转化生长因子（ETGF）和白细胞介素10（IL-10）。LIF/LIF受体相互作用诱导CD 8 + TRL产生ETGF和IL-10。虽然IL-10诱导对CD 8 + TRLs的免疫效应很重要，但ETGF提供了直接的神经保护。中风后静脉内转移CD 8 + TRLs减少了梗死，促进了年轻雄性或老年小鼠的长期神经恢复。因此，这些独特的CD 8 + TRL可作为早期反应者来对抗中风，为临床转化提供新的视角。
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.