m(6)A methyltransferase METTL3 programs CD4(+) T-cell activation and effector T-cell differentiation in systemic lupus erythematosus

BACKGROUND: Systemic lupus erythematosus (SLE) is an autoimmune disorder in which excessive CD4(+) T-cell activation and imbalanced effector T-cell differentiation play critical roles. Recent studies have implied a potential association between posttranscriptional N6-methyladenosine (m(6)A) modification and CD4(+) T-cell-mediated humoral immunity. However, how this biological process contributes to lupus is not well understood. In this work, we investigated the role of the m(6)A methyltransferase like 3 (METTL3) in CD4(+) T-cell activation, differentiation, and SLE pathogenesis both in vitro and in vivo. METHODS: The expression of METTL3 was knocked down and METTL3 enzyme activity was inhibited using siRNA and catalytic inhibitor, respectively. In vivo evaluation of METTL3 inhibition on CD4(+) T-cell activation, effector T-cell differentiation, and SLE pathogenesis was achieved using a sheep red blood cell (SRBC)-immunized mouse model and a chronic graft versus host disease (cGVHD) mouse model. RNA-seq was performed to identify pathways and gene signatures targeted by METTL3. m(6)A RNA-immunoprecipitation qPCR was applied to confirm the m(6)A modification of METTL3 targets. RESULTS: METTL3 was defective in the CD4(+) T cells of SLE patients. METTL3 expression varied following CD4(+) T-cell activation and effector T-cell differentiation in vitro. Pharmacological inhibition of METTL3 promoted the activation of CD4(+) T cells and influenced the differentiation of effector T cells, predominantly Treg cells, in vivo. Moreover, METTL3 inhibition increased antibody production and aggravated the lupus-like phenotype in cGVHD mice. Further investigation revealed that catalytic inhibition of METTL3 reduced Foxp3 expression by enhancing Foxp3 mRNA decay in a m(6)A-dependent manner, hence suppressing Treg cell differentiation. CONCLUSION: In summary, our findings demonstrated that METTL3 was required for stabilizing Foxp3 mRNA via m(6)A modification to maintain the Treg differentiation program. METTL3 inhibition contributed to the pathogenesis of SLE by participating in the activation of CD4(+) T cells and imbalance of effector T-cell differentiation, which could serve as a potential target for therapeutic intervention in SLE. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s10020-023-00643-4.