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^(6)A)methyltransferase Mettl3 during CD8^(+)T...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^(6)A)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^(6)A-dependent manner,subsequently affecting memory formation and the secondary response of CD8^(+)T cells.Our combined RNA-seq and m^(6)AmiCLIP-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^(6)A-dependent manner and underscores the importance of m^(6)A modification during CD8^(+)T cell response.展开更多
基金the National Natural Science Foundation of China(32130039,31970831,81970541,31960151,and 31630038)the National Key Research and Development Program of China(2017YFA0104401)+3 种基金the Pinduoduo-China Agricultural University Research Fund(PC2023B01011)Frontiers Science Center for Molecular Design Breeding(MOE),Chinese Universities Scientific Fund(2022TC030 and 2021TC087)the Project for Extramural Scientists of State Key Laboratory of Agrobiotechnology from China Agricultural University(2021SKLAB6-3 and 2021SKLAB6-4)the Collaborative Innovation Center of Chinese Ministry of Education(2020-39)。
文摘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^(6)A)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^(6)A-dependent manner,subsequently affecting memory formation and the secondary response of CD8^(+)T cells.Our combined RNA-seq and m^(6)AmiCLIP-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^(6)A-dependent manner and underscores the importance of m^(6)A modification during CD8^(+)T cell response.
基金the Youth Science Fund Project of the National Natural Science Foundation of China(Grant No.12102358)the China Postdoctoral Science Foundation(Grant No.2020M692617)+3 种基金the Fundamental Research Funds for the Central Universities(Grant No.3102021HHZY030008)Natural Science Foundation of Chongqing of China(Grant No.cstc2021jcyj-msxmX0393)the Young Talent Fund of Association for Science and Technology in Shaanxi,China(Grant No.20220512)Advanced Space Propulsion Laboratory of BICE and Beijing Engineering Research Center of Efficient and Green Aerospace Propulsion Technology(Grant No.LabASP-2022-05).
