【摘要】 Efficient immune responses rely on the proper differentiation of CD8~+T cells into effector and memory cells.Here,we show a critical requirement of N~6-Methyladenosine(m~6A) methyltransferase Mettl3 during CD8~+ T cell responses upon acute viral infection.Conditional deletion of Mettl3 in CD8~+ T cells impairs effector expansion and terminal differentiation in an m~6A-dependent manner,subsequently affecting memory formation and the secondary response of CD8~+T cells.Our combined RNA-seq and m~6AmiCLIP-seq analyses reveal that Mettl3 deficiency broadly impacts the expression of cell cycle and transcriptional regulators.Remarkably,Mettl3 binds to the Tbx21 transcript and stabilizes it,promoting effector differentiation of CD8~+T cells.Moreover,ectopic expression of T-bet partially restores the defects in CD8~+T cell differentiation in the absence of Mettl3.Thus,our study highlights the role of Mettl3 in regulating multiple target genes in an m~6A-dependent manner and underscores the importance of m~6A modification during CD8~+ T cell response.更多还原

【Abstract】 Efficient immune responses rely on the proper differentiation of CD8~+T cells into effector and memory cells.Here,we show a critical requirement of N~6-Methyladenosine(m~6A) methyltransferase Mettl3 during CD8~+ T cell responses upon acute viral infection.Conditional deletion of Mettl3 in CD8~+ T cells impairs effector expansion and terminal differentiation in an m~6A-dependent manner,subsequently affecting memory formation and the secondary response of CD8~+T cells.Our combined RNA-seq and m~6AmiCLIP-seq analyses reveal that Mettl3 deficiency broadly impacts the expression of cell cycle and transcriptional regulators.Remarkably,Mettl3 binds to the Tbx21 transcript and stabilizes it,promoting effector differentiation of CD8~+T cells.Moreover,ectopic expression of T-bet partially restores the defects in CD8~+T cell differentiation in the absence of Mettl3.Thus,our study highlights the role of Mettl3 in regulating multiple target genes in an m~6A-dependent manner and underscores the importance of m~6A modification during CD8~+ T cell response.更多还原