Downregulation of Mettl14-mediated m6A modification prevents allograft survival by elevating the stabilization of Sema4D mRNA and disrupting the function of regulatory T cells
Gaoping Zhao1,2, Yanzhuo Liu1,2, Qiang Fu2, YingLin Yuan1,2, Yuanyuan Cui1,2, Yanlin Zhang1,2, Lu Yang3.
1Department of Gastrointestinal Surgery, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, People's Republic of China; 2Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, People's Republic of China; 3Department of Neurology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, People's Republic of China
Regulatory T cells (Tregs) exert potent effects in preventing transplant rejection. Recently, N6-methyladenosine (m6A) has been identified as a key posttranscriptional regulator of FoxpP3, contributing significantly to the genetic elements governing Treg function. However, how m6A affects Tregs after transplantation remains unclear. In this study, we found that Mettl14 deficiency promoted Th17 cell proliferation and allograft rejection in mice after islet transplantation. MeRIP and mRNA sequencing analysis revealed that Mettl14 knockout affected the expression of genes such as Sema4D, which were related to T cell homeostasis. Mettl14 knockdown impeded SEMA4D mRNA m6A modification and promoted SEMA4D mRNA expression markedly. Additionally, METTL14-mediated SEMA4D mRNA degradation relied on the Mettl14-YTHDF2-dependent pathway. Besides, METTL14 deficiency disrupted the function of Treg cells partly through the PAK-STAT5 signals pathway. Mettl14 knockdown Tregs lack of Sema4D inhibited T cell proliferation in vitro and better-prevented allograft rejection. Clinical data showed that recipients with low Sema4D expression had better survival after kidney Transplantation, YTHDF2 was a protective factor for allograft survival. Our data suggest that the downregulation of METTL14 leads to enhanced stability of Sema4D, impeding the allograft survival.
[1] N6-methyladenosine
[2] Treg function
[3] Sema4D
[4] Mettle 14
[5] allograft acceptance
