Purinergic signaling by TCRαβ+ double-negative T regulatory cells ameliorates liver ischemia-reperfusion injury

Hua Jin; Mingyang Li; Xiyu Wang; Lu Yang; Xinjie Zhong; Zihan Zhang; Xiaotong Han; Jingjing Zhu; Mengyi Li; Songlin Wang; Simon C Robson; Guangyong Sun; Dong Zhang

doi:10.1016/j.scib.2024.11.039

Purinergic signaling by TCRαβ⁺ double-negative T regulatory cells ameliorates liver ischemia-reperfusion injury

Sci Bull (Beijing). 2024 Nov 28:S2095-9273(24)00871-5. doi: 10.1016/j.scib.2024.11.039. Online ahead of print.

Authors

Hua Jin¹, Mingyang Li², Xiyu Wang³, Lu Yang⁴, Xinjie Zhong³, Zihan Zhang², Xiaotong Han³, Jingjing Zhu³, Mengyi Li⁴, Songlin Wang⁵, Simon C Robson⁶, Guangyong Sun⁷, Dong Zhang⁸

Affiliations

¹ 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.
² Immunology Research Center for Oral and Systemic Health, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China.
³ 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.
⁴ General Surgery Department, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China.
⁵ Beijing Laboratory of Oral Health, Capital Medical University School of Basic Medicine, Beijing 100069, China.
⁶ Center for Inflammation Research, Department of Anesthesia, Critical Care & Pain Medicine, and Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA. Electronic address: srobson@bidmc.harvard.edu.
⁷ 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. Electronic address: sungy@ccmu.edu.cn.
⁸ 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; General Surgery Department, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China,; Beijing Laboratory of Oral Health, Capital Medical University School of Basic Medicine, Beijing 100069, China. Electronic address: zhangd@ccmu.edu.cn.

PMID: 39658411
DOI: 10.1016/j.scib.2024.11.039

Abstract

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.

Keywords: A2AR; Adenosine; CD39; Double-negative T regulatory cells; Hepatic ischemia and reperfusion injury.