Downregulation of N6-Methyladenosine (m6A) Methylation of Sema4D mRNA Contributes to Treg Dysfunction and Allograft Rejection

Yanzhuo Liu; Qiang Fu; Maozhu Yang; Jianli Xu; Zili Zhou; Xingmin Chen; Yanling Zhang; Hao Yuan; Guiqing Jia; Shu He; Lu Yang; Gaoping Zhao

doi:10.1016/j.ajt.2025.01.017

Downregulation of N6-Methyladenosine (m6A) Methylation of Sema4D mRNA Contributes to Treg Dysfunction and Allograft Rejection

Am J Transplant. 2025 Jan 21:S1600-6135(25)00023-1. doi: 10.1016/j.ajt.2025.01.017. Online ahead of print.

Authors

Yanzhuo Liu¹, Qiang Fu², Maozhu Yang³, Jianli Xu⁴, Zili Zhou⁵, Xingmin Chen⁴, Yanling Zhang⁶, Hao Yuan⁷, Guiqing Jia⁵, Shu He⁴, Lu Yang⁸, Gaoping Zhao⁹

Affiliations

¹ Department of Gastrointestinal Surgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan Province, China; Department of Oncology, Medical Research Center, Affiliated Hospital of Southwest Jiao Tong University, The Third People's Hospital of Chengdu, Chengdu, Sichuan Province, China.
² Organ Transplantation Center, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, Sichuan Province, China; Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Chengdu, Sichuan Province, China.
³ Department of Hepatobiliary-Pancreatic Surgery, Cell Transplantation Center, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan Province, China.
⁴ Institute of Neurology, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan Province, China.
⁵ Department of Gastrointestinal Surgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan Province, China.
⁶ Department of Gastrointestinal Surgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan Province, China; Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Chengdu, Sichuan Province, China.
⁷ The Seventh People's Hospital of Chengdu affiliated Cancer Hospital of Chengdu Medical College, Chengdu, Sichuan Province, China.
⁸ Institute of Neurology, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan Province, China. Electronic address: [email protected].
⁹ Department of Gastrointestinal Surgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan Province, China; Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Chengdu, Sichuan Province, China. Electronic address: [email protected].

PMID: 39848338
DOI: 10.1016/j.ajt.2025.01.017

Abstract

Regulatory T cells (Tregs) has been shown to be involved in the induction of transplantation tolerance in numerous models. Our previous work demonstrated that METTL14 loss impaired Treg function and hindered the establishment of transplantation tolerance. However, the underlying mechanisms remain unclear. In this study, we found that METTL14 knockdown in Tregs significantly impaired their regulatory function, leading to poor allograft function and accelerated transplant rejection. Through MeRIP and mRNA sequencing approaches, we discovered that METTL14 deficiency fostered the expression of Sema4D mRNA, a key semaphorin family member with immunoregulatory activity. Methylation of target adenosines reduced Sema4D mRNA degradation, a process mediated by the METTL14-YTHDF2 axis. Inhibition of Sema4D suppressed its interaction with its receptor, thereby preserving Treg immunoregulation capability and prolonging allograft survival through the PAK-STAT5 signaling pathway. Importantly, Sema4D expression in kidney transplant biopsies were negatively correlated with renal allograft survival. In summary, our findings suggest that METTL14 deficiency in Tregs leads to transplant rejection and reveal for the first time that Sema4D may serve as a potential therapeutic target to enhance Treg function in transplantation.

Keywords: METTL14-mediated m6A; Sema4D; Transplant rejection; Treg.