T‐cell–derived extracellular vesicles regulate B‐cell IgG production via pyruvate kinase muscle isozyme 2
T‐cell–derived extracellular vesicles regulate B‐cell IgG production via pyruvate kinase muscle isozyme 2
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DOI：
10.1096/fj.201900863r
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发表时间：
2019-11
期刊：
影响因子：
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通讯作者：
Juan Yang;Guohui Dang;Si-lin Lü;Hui-ying Liu;Xiaolong Ma;Lulu Han;Jiacheng Deng;Yutong Miao
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文献类型：
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作者：
Juan Yang;Guohui Dang;Si-lin Lü;Hui-ying Liu;Xiaolong Ma;Lulu Han;Jiacheng Deng;Yutong Miao
淋巴细胞之间的细胞间通讯在许多免疫应答中起着重要作用。之前，我们证明了高同型半胱氨酸（HHcy）通过丙酮酸激酶肌肉同工酶2（PKM 2）诱导T细胞胞内糖酵解-脂肪生成重编程和IFN-γ分泌，以加速动脉粥样硬化。通常，B细胞在抗体应答中部分地获得T细胞的帮助。然而，T细胞中的PKM 2活化是否调节B细胞抗体产生尚不清楚。细胞外囊泡（EV）是重要的细胞通讯媒介。在这里，我们发现PKM 2激活剂TEPP 46刺激的T细胞来源的EV促进B细胞IgG分泌。相反，从PKM 2-null T细胞分泌的EV被内化到B细胞中，并显著抑制B-细胞线粒体编程、活化和IgG产生。从机制上讲，脂质组学分析表明，PKM 2激活的T细胞EV中增加的神经酰胺主要是这些EV诱导的B细胞IgG分泌增强的原因。最后，将量子点（QD）与PKM 2-null T细胞EV和抗CD 19抗体包装在一起，以发挥B-细胞靶向作用并抑制IgG产生，最终改善体内HHcy加速的动脉粥样硬化。因此，T细胞中PKM 2介导的EV神经酰胺可能是T细胞调节的B细胞IgG产生的重要货物，并且QD-CD 19-PKM 2-null T细胞EV具有治疗B细胞过度活化相关疾病的高潜力。杨杰，天啊，G.，Lü，S.，刘洪，妈，X.，汉湖，加-地邓，J.，苗，Y.，Li，X.，Shao，F.，江，C.徐，Q，王，X.，Feng，J. T细胞衍生的细胞外囊泡通过丙酮酸激酶肌肉同工酶2调节B细胞IgG的产生。FASEB J. 33，12780-12799（2019）。www.fasebj.org
Intercellular communication between lymphocytes plays a fundamental role in numerous immune responses. Previously, we demonstrated that hyperhomocysteinemia (HHcy) induced T cell intracellular glycolytic‐lipogenic reprogramming and IFN‐γ secretion via pyruvate kinase muscle isozyme 2 (PKM2) to accelerate atherosclerosis. Usually, B cells partially obtain help from T cells in antibody responses. However, whether PKM2 activation in T cells regulates B cell antibody production is unknown. Extracellular vesicles (EVs) are important cellular communication vehicles. Here, we found that PKM2 activator TEPP46‐stimulated T‐cell–derived EVs promoted B‐cell IgG secretion. Conversely, EVs secreted from PKM2‐null T cells were internalized into B cells and markedly inhibited B‐cell mitochondrial programming, activation, and IgG production. Mechanistically, lipidomics analyses showed that increased ceramides in PKM2‐activated T‐cell EVs were mainly responsible for enhanced B cell IgG secretion induced by these EVs. Finally, quantum dots (QDs) were packaged with PKM2‐null T cell EVs and anti‐CD19 antibody to exert B‐cell targeting and inhibit IgG production, eventually ameliorating HHcy‐accelerated atherosclerosis in vivo. Thus, PKM2‐mediated EV ceramides in T cells may be an important cargo for T‐cell–regulated B cell IgG production, and QD‐CD19‐PKM2‐null T cell EVs hold high potential to treat B cell overactivation‐related diseases.—Yang, J., Dang, G., Lü, S., Liu, H., Ma, X., Han, L., Deng, J., Miao, Y., Li, X., Shao, F., Jiang, C., Xu, Q., Wang, X., Feng, J. T‐cell‐derived extracellular vesicles regulate B‐cell IgG production via pyruvate kinase muscle isozyme 2. FASEB J. 33, 12780–12799 (2019). www.fasebj.org