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

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.