CD4+T cell-mediated acute rejection remains a major factor that affects the early survival of transplanted organs post-transplantation. Here, we reveal that nuclear receptor subfamily 4 Group A member 1 (Nr4A1) was upregulated during cardiac allograft rejection and that the increased Nr4A1 was primarily localized in intragraft-infiltrating CD4+T cells. Nr4A1 acts as a transcription factor with an important role in CD4+T cell apoptosis, differentiation and T cell dysfunction, which indicates that Nr4A1 may play a critical role in transplant rejection. Cytosporone B (Csn-B) is a naturally occurring agonist of Nr4A1, and the role of Csn-B in the physiological process of cardiac rejection is poorly defined. This study constructed an acute rejection model of abdominal heterotopic cardiac transplantation in mice and investigated whether Csn-B could attenuate acute transplant rejection by modulating the CD4+T lymphocyte response. The results showed that Csn-B prolonged murine cardiac allograft survival and reduced inflammation in allografts. Subsequently, it was confirmed that Csn-B functions by inducing non-Treg apoptosis and promoting Treg cell differentiation. Finally, we also confirmed that Csn-B attenuates acute rejection by directly targeting Nr4A1 in CD4+T cells. Our data suggest that Csn-B is a promising novel therapeutic approach for acute cardiac allograft rejection.

中文翻译：

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Cytosporone B (Csn-B) 是一种 NR4A1 激动剂，通过诱导 CD4+T 细胞的差异性凋亡来减轻急性心脏同种异体移植排斥。


CD4+T细胞介导的急性排斥反应仍然是影响移植器官移植后早期存活的主要因素。在这里，我们揭示了核受体亚家族 4 A 组成员 1 (Nr4A1) 在心脏同种异体移植排斥过程中上调，并且增加的 Nr4A1 主要位于移植物内浸润的 CD4+T 细胞中。 Nr4A1作为转录因子，在CD4+T细胞凋亡、分化和T细胞功能障碍中发挥重要作用，这表明Nr4A1可能在移植排斥中发挥关键作用。 Cytosporone B (Csn-B) 是一种天然存在的 Nr4A1 激动剂，Csn-B 在心脏排斥的生理过程中的作用尚不清楚。本研究构建了小鼠腹部异位心脏移植的急性排斥反应模型，并探讨Csn-B是否可以通过调节CD4+T淋巴细胞反应来减轻急性移植排斥反应。结果表明，Csn-B 可以延长小鼠同种异体心脏移植物的存活时间并减少同种异体移植物中的炎症。随后，证实Csn-B通过诱导非Treg细胞凋亡和促进Treg细胞分化发挥作用。最后，我们还证实 Csn-B 通过直接靶向 CD4+T 细胞中的 Nr4A1 来减轻急性排斥反应。我们的数据表明，Csn-B 是治疗急性心脏同种异体移植排斥反应的一种有前途的新型治疗方法。