Acute ischemic stroke, one of the leading causes of death and disability all around world, induces profound activation of the lymphocytes which could interact with the ischemic brain injury and significantly impact stroke pathology. Meanwhile, stroke is common in elderly people who are at high risk of malignant cancer. Since the lymphocytic immune response participates both in tumor progression and brain injuries produced by ischemia, there might be a noteworthy reciprocal interaction between stroke and cancer. For example, the ischemic brain could induce an immunosuppressive response that may promote cancer progression and trigger fetal infections which seriously affect the prognosis and survival of stroke patients. Therefore, we need more precise indicators to maintain the balance of the post-stroke immunity and predict the outcome of cancer-bearing stroke patients receiving immunotherapies.

Lymphocytes play an important role in the pathological mechanism of adaptive immune response after stroke. Within hours of transient middle cerebral artery occlusion (tMCAO), T lymphocytes infiltrate into the brain and gather near the boundary of the infarction area. In particular, CD4⁺ T cells infiltrate into the ischemic brain within 24 h and peaked at 72 h after reperfusion, which induce brain injury and exacerbate neuroinflammation.¹ Cytotoxic CD8⁺ T cells can be recruited into the brain as early as 3 h after stroke and can exacerbate the neurological deficits up to weeks after ischemic stroke by inducing demyelination of the neuronal axons.² To avoid overactivation of the neuroinflammation, the body has self-limiting mechanism to counteract the T-cell-mediated immune response in the brain. The activation of the immune regulatory cells, such as regulatory T cells (Tregs) and regulatory B cells (Bregs), represents one of the critical self-limiting mechanism.^{3, 4} Regulatory B cell is a subset of B lymphocytes with immunomodulation function, which plays an important role in maintaining immune tolerance and suppressing harmful immune response. Bregs can limit CNS inflammation and neurologic deficits in murine experimental stroke.⁴ CD4⁺Tregs account for only 5% of the CD4⁺ T cells and are associated with a variety of inflammatory response pathways and have neuroprotection effects on inflammatory responses after ischemic stroke, and IL-10 signaling is essential in the immunomodulation of Treg cells.⁵ Hence, Treg cells are significant modulators of inflammatory-induced brain injury after ischemic stroke. CD8⁺ Treg is a small subset of T cells that is obtaining increasing attention in recent years. It has been shown to play important roles in controlling several autoimmune diseases, such as CD4⁺-cell-induced colitis, experimental autoimmune encephalomyelitis, experimental inflammatory bowel disease, and autoimmune type 1 diabetes. However, the role of CD8⁺ Tregs in ischemic brain injury has not been reported.

In the paper by Li et al.,⁶ the percentage of circulating T cells, CD4⁺ T cells, CD8⁺ T cells, double-negative T cells (DNTs), CD4⁺Tregs, CD8⁺Tregs, B cells, and Bregs in the peripheral blood were examined both at admission and 3 months after stroke by enrolling a total of 210 acute ischemic stroke patients and 876 healthy controls. The researchers found that the number of B cells, Bregs, and CD8⁺Tregs increased significantly, while CD4⁺ Tregs dropped and soon reversed after ischemic stroke. Notably, CD4⁺Tregs, CD8⁺ Tregs, and DNTs exhibited high correlation with the infarct volume and neurological scores of stroke patients. The percentage of CD4⁺ Tregs within lymphocytes displayed high correlations with both acute and long-term neurological outcomes, which exhibited a great independent predictive ability. Our previous study reported that adoptive transfer of CD4⁺Tregs can protect the integrity of the blood-brain barrier and thus attenuates the ischemic brain injury and reduces the risk of tPA-induced hemorrhagic transformation after stroke.^{7, 8} The participation of adaptive immunity in the pathological process of ischemia and reperfusion and the protective effect of regulatory lymphocytes in stroke is proved by many researchers. There is massive accumulation of Treg cells in the mouse brain after ischemic stroke, and this potentiates neurological recovery during the chronic phase of ischemic brain injury.³ Stroke induced significant bilateral B-cell diapedesis into remote brain regions and mediated motor and cognitive recovery⁹ Although much has been learned on the interaction between immune responses and damaged brain and factors affecting neurological outcome, it is still unclear how the regulatory lymphocytic responses develop in the brain in the short term and long term after stroke. In addition, biomarkers which could be applied directly in clinic still remain deficient. Identifying specific biomarkers of the lymphocytic responses after stroke could guide the clinical management, attenuate long-term neurological deficit, and improve long-term life quality of stroke patients.

All the above evidence strongly supports CD4⁺ Tregs could serve as a sensitive biomarker and also a potential therapeutic target for stroke therapy. However, as an immune suppressive T-cell subset, CD4⁺Tregs could exacerbate cancer progression, which raises a concern for the translation of Treg-based stroke therapy, especially in cancer-bearing stroke patients. Recent evidence suggests that in cancer-bearing stroke mice, CD4⁺ Tregs could be recruited into the tumor, thus attenuate their protection of the blood-brain barrier after stroke.¹⁰ Importantly, with the aging of the population, the number of cancer patients is continuously rising. Therefore, cancer-related immune response is emerging as a noteworthy clinical issue for stroke patients. Considering the importance of the regulatory lymphocytes in the severity of ischemic stroke, developing blood-based biomarkers targeting above mentioned regulatory immune cells could provide valuable and easily accessible predictive tool to predict stroke outcome and improve stroke patient management.

急性缺血性中风是世界范围内导致死亡和残疾的主要原因之一，它诱导淋巴细胞的深度激活，这可能与缺血性脑损伤相互作用并显着影响中风病理学。同时，中风在罹患恶性肿瘤的高风险老年人中很常见。由于淋巴细胞免疫反应参与肿瘤进展和缺血产生的脑损伤，因此中风和癌症之间可能存在值得注意的相互作用。例如，缺血性大脑可以诱导免疫抑制反应，从而促进癌症进展并引发胎儿感染，从而严重影响中风患者的预后和生存。所以，

淋巴细胞在脑卒中后适应性免疫反应的病理机制中起重要作用。在短暂的大脑中动脉闭塞 (tMCAO) 的数小时内，T 淋巴细胞浸润到大脑并聚集在梗塞区域的边界附近。特别是CD4 ⁺ T细胞在24小时内浸润到缺血性脑中，再灌注后72小时达到峰值，从而诱发脑损伤并加剧神经炎症。¹细胞毒性 CD8 ⁺ T 细胞最早可在中风后 3 小时被募集到大脑中，并且可通过诱导神经元轴突的脱髓鞘作用在缺血性中风后数周内加剧神经功能缺损。²为了避免神经炎症过度激活，身体具有自我限制机制来抵消大脑中 T 细胞介导的免疫反应。免疫调节细胞的激活，例如调节性 T 细胞 (Tregs) 和调节性 B 细胞 (Bregs)，代表了关键的自限机制之一。^{3, 4}调节性B细胞是具有免疫调节功能的B淋巴细胞亚群，在维持免疫耐受和抑制有害免疫反应方面具有重要作用。Bregs 可以限制小鼠实验性中风的 CNS 炎症和神经功能缺损。^4个CD4 ⁺ Tregs只占CD4+的5 ^%T 细胞与多种炎症反应通路相关，对缺血性卒中后的炎症反应具有神经保护作用，IL-10 信号传导在 Treg 细胞的免疫调节中至关重要。⁵因此，Treg 细胞是缺血性中风后炎症性脑损伤的重要调节剂。CD8 ⁺ Treg 是 T 细胞的一小部分，近年来受到越来越多的关注。它已被证明在控制多种自身免疫性疾病中发挥重要作用，例如 CD4 ⁺细胞诱导的结肠炎、实验性自身免疫性脑脊髓炎、实验性炎症性肠病和自身免疫性 1 型糖尿病。但是，CD8 ^+的作用 尚未报道缺血性脑损伤中的 Tregs。

在 Li 等人的论文中，⁶循环 T 细胞、CD4 ⁺ T 细胞、CD8 ⁺ T 细胞、双阴性 T 细胞 (DNT)、CD4 ⁺ Tregs、CD8 ⁺ Tregs、B 细胞和 Bregs 在共纳入 210 名急性缺血性中风患者和 876 名健康对照者，在入院时和中风后 3 个月检查外周血。研究人员发现，缺血性中风后 B 细胞、Bregs 和 CD8 ⁺ Tregs 的数量显着增加，而 CD4 ⁺ Tregs 下降并很快逆转。值得注意的是，CD4 ⁺ Tregs、CD8 ⁺Tregs 和 DNTs 与中风患者的梗死体积和神经系统评分具有高度相关性。^{淋巴细胞中 CD4 +} Tregs的百分比与急性和长期神经系统结果高度相关，具有很强的独立预测能力。我们之前的研究报告说，过继转移 CD4 ⁺ Tregs 可以保护血脑屏障的完整性，从而减轻缺血性脑损伤并降低 tPA 诱导的中风后出血性转化的风险。^7、8适应性免疫参与缺血再灌注的病理过程以及调节性淋巴细胞对脑卒中的保护作用已被众多研究者证明。缺血性中风后小鼠大脑中存在大量 Treg 细胞积聚，这增强了缺血性脑损伤慢性期的神经功能恢复。³中风诱导显着的双侧 B 细胞渗出进入大脑偏远区域并介导运动和认知恢复⁹尽管在免疫反应与受损大脑之间的相互作用以及影响神经系统结果的因素方面已经了解了很多，但仍不清楚中风后短期和长期大脑中调节性淋巴细胞反应是如何发展的。此外，可直接应用于临床的生物标志物仍然缺乏。识别中风后淋巴细胞反应的特异性生物标志物可以指导临床管理，减轻长期神经功能缺损，提高中风患者的长期生活质量。

所有上述证据都强烈支持 CD4 ⁺ Tregs 可以作为敏感的生物标志物，也是中风治疗的潜在治疗靶点。然而，作为一种免疫抑制性 T 细胞亚群，CD4 ⁺ Tregs 可能会加剧癌症进展，这引起了对基于 Treg 的中风治疗的转化的关注，特别是在患有癌症的中风患者中。最近的证据表明，在患有癌症的中风小鼠中，CD4 ⁺ Tregs 可以被募集到肿瘤中，从而减弱它们对中风后血脑屏障的保护作用。¹⁰重要的是，随着人口老龄化，癌症患者的数量不断增加。因此，癌症相关的免疫反应正在成为中风患者值得注意的临床问题。考虑到调节性淋巴细胞在缺血性卒中严重程度中的重要性，开发针对上述调节性免疫细胞的基于血液的生物标志物可以提供有价值且易于获得的预测工具，以预测卒中结果并改善卒中患者管理。