CD38 promotes regulatory T Cell survival and immunosuppression via calcium/Ras/GGT1 pathway activation to attenuate ROS post-transplantation
Yunjie Lu5,6, Jinren Zhou1,3, Qufei Qian2, Yu Li2, Qing Shao2, Yuan Liang2, Ziyan Song2, Bo Zhou4, Tianning Huang2, Ji Gao2, Xiaozhang Xu2, Qiuyang Chen2, Xiangyu Li2, Zeyu Hou6, Lin Zhuang5, Liping Zhao1.
1Nanjing Medical University Friendship Plastic Surgery Hospital, Nanjing Medical University Friendship Plastic Surgery Hospital, Nanjing, People's Republic of China; 2Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University and Research Unit of Liver Transplantati, Nanjing, People's Republic of China; 3Department of vascular surgery, the second affiliated hospital of Zhejiang University School of Medicine, Hangzhou, People's Republic of China; 4Department of General Surgery, Ningbo Medical Center LiHuiLi Hospital (The Affiliated Lihuili Hospital of Ningbo University), Ningbo, People's Republic of China; 5Department of General Surgery, Wujin Affiliated Hospital of Jiangsu University and The Wujin clinical college of Xuzhou medical uni, Changzhou, People's Republic of China; 6Department of General surgery, The First Affiliated Hospital of Soochow University, Suzhou, People's Republic of China
Organ transplantation necessitates lifelong immunosuppressive therapy to maintain intrahepatic immune homeostasis and mitigate transplant-related immune-mediated adverse events. Regulatory T cells (Tregs) are now understood to play an essential role in inducing immune tolerance. This study aimed to investigate the effect and mechanism of CD38 on Treg immunoregulatory function after organ transplantation. Results demonstrated that CD38 enhanced Treg suppressive capacity and survival by promoting oxidative phosphorylation (OXPHOS) and attenuating reactive oxygen species (ROS) production. Integrated proteomic, metabolomic, and biochemical analyses revealed that CD38 activated calcium signaling, subsequently initiating Ras/NF-B signaling. Gamma-glutamyl transferase 1 (GGT1), a transcriptional target of NF-B, was upregulated in CD38hi Tregs. GGT1 facilitated Treg survival and ROS resistance by degrading exogenous glutathione (GSH) and augmenting intracellular glutamate, cysteine, and glycine levels, thereby indirectly stimulating endogenous GSH synthesis. In humanized xenogeneic graft-versus-host disease and skin transplantation models, CD38hi Treg administration was found to attenuate target organ inflammatory infiltration and prolonged survival. This study elucidates the role of CD38 in post-transplantation immune tolerance and identifies CD38 as a potential therapeutic target for enhancing Treg-mediated immunosuppression.
2023 Jiangsu Science and Technology Association youth Science and technology talent lifting project (JSTJ-2023-XH015). Ningbo Natural Science Foundation (Grant No.2023J231). The Science and Technology Project of Changzhou Health Commission (QN202338).
[1] Tregs
[2] CD38
[3] Organ transplantation
[4] Immunosuppression
[5] Immune tolerance