Jin Hua, Li Mingyang, Wang Xiyu, Yang Lu, Zhong Xinjie, Zhang Zihan, Han Xiaotong, Zhu Jingjing, Li Mengyi, Wang Songlin, Robson Simon C, Sun Guangyong, Zhang Dong
Immunology Research Center for Oral and Systemic Health, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China; Medical Research Center, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China; Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China.
Immunology Research Center for Oral and Systemic Health, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China.
Sci Bull (Beijing). 2025 Jan 30;70(2):241-254. doi: 10.1016/j.scib.2024.11.039. Epub 2024 Nov 28.
Hepatic ischemia-reperfusion injury (HIRI) is an important cause of liver injury following liver transplantation and major resections, and neutrophils are the key effector cells in HIRI. Double-negative T regulatory cells (DNT) are increasingly recognized as having critical regulatory functions in the immune system. Whether DNT expresses distinct immunoregulatory mechanisms to modulate neutrophils, as in HIRI, remains largely unknown. In this study, we found that murine and human DNT highly expressed CD39 that protected DNT from extracellular ATP-induced apoptosis and generated adenosine in tandem with CD73, to induce high levels of neutrophil apoptosis. Furthermore, extracellular adenosine enhanced DNT survival and suppressive function by upregulating survivin and NKG2D expression via the A2AR/pAKT/FOXO1 signaling pathway. Adoptive transfer of DNT ameliorated HIRI in mice through the inhibition of neutrophils in a CD39-dependent manner. Lastly, the adoptive transfer of A2ar DNT validated the importance of adenosine/A2AR signaling, in promoting DNT survival and immunomodulatory function to protect against HIRI in vivo. In conclusion, purinergic signaling is crucial for DNT homeostasis in HIRI. Augmentation of CD39 or activation of A2AR signaling in DNT may provide novel therapeutic strategies to target innate immune disorders.
肝缺血再灌注损伤（HIRI）是肝移植和肝大部切除术后肝损伤的重要原因，中性粒细胞是HIRI中的关键效应细胞。双阴性T调节细胞（DNT）越来越被认为在免疫系统中具有关键的调节功能。在HIRI中，DNT是否表达独特的免疫调节机制来调节中性粒细胞，在很大程度上仍不清楚。在本研究中，我们发现小鼠和人类DNT高表达CD39，其保护DNT免受细胞外ATP诱导的凋亡，并与CD73协同生成腺苷，从而诱导高水平的中性粒细胞凋亡。此外，细胞外腺苷通过A2AR/pAKT/FOXO1信号通路上调生存素和NKG2D的表达，增强DNT的存活和抑制功能。DNT的过继转移通过以CD39依赖的方式抑制中性粒细胞，改善了小鼠的HIRI。最后，A2ar DNT的过继转移证实了腺苷/A2AR信号在促进DNT存活和免疫调节功能以保护小鼠免受体内HIRI方面的重要性。总之，嘌呤能信号对于HIRI中DNT的稳态至关重要。增强DNT中的CD39或激活A2AR信号可能为针对先天性免疫紊乱提供新的治疗策略。
