摘要
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 CD39that 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.
基金
supported by the grants from the National Natural Science Foundation of China(81970503,82100670,82202021and 82270606)
Chinese Institutes for Medical Research
Beijing(CX24PY16)
R&D Program of Beijing Municipal Education Commission(KZ202210025036)
Beijing Municipal Administration of Hospitals’Ascent Plan(DFL20220103)
Beijing Nova Program(Z211100002121036)
Youth Beijing Scholar(035)and the Reform and Development Program of Beijing Institute of Respiratory Medicine(Ggyfz202403)
Generation of reagents and mutant mice are also supported by the National Institutes of Health(R01 DK108894
R21 CA164970 and R21 CA221702)
Department of Defense Award W81XWH-16-0464。
