Mettl3-dependent m6A modification is essential for effector differentiation and memory formation of CD8+T cells

Wenhui Guo ¹Zhao Wang ¹Yajiao Zhang ¹Yashu Li ²Qian Du ³Tiantian Zhang ²Jin Hu ²Yingpeng Yao ¹Jiarui Zhang ¹Yingdi Xu ¹Xiao Cui ¹Zhen Sun ¹Menghao You ¹Guotao Yu ¹Haojian Zhang ²Xuguang Du ¹Jingyu Xu ³Shuyang Yu⁴

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作者信息

1. State Key Laboratory of Animal Biotech Breeding,College of Biological Sciences,China Agricultural University,Beijing 100193,China
2. Frontier Science Center for Immunology and Metabolism,Medical Research Institute,School of Medicine,Wuhan University,Wuhan 430071,China
3. The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University,Zunyi 563000,China
4. State Key Laboratory of Animal Biotech Breeding,College of Biological Sciences,China Agricultural University,Beijing 100193,China;The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University,Zunyi 563000,China
折叠

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 N6-Methyladenosine(m6A)methyltransferase Mettl3 dur-ing CD8+T cell responses upon acute viral infection.Conditional deletion of Mettl3 in CD8+T cells impairs effector expansion and terminal differentiation in an m6A-dependent manner,subsequently affecting memory formation and the secondary response of CD8+T cells.Our combined RNA-seq and m6A-miCLIP-seq analyses reveal that Mettl3 deficiency broadly impacts the expression of cell cycle and tran-scriptional regulators.Remarkably,Mettl3 binds to the Tbx21 transcript and stabilizes it,promoting effec-tor 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 reg-ulating multiple target genes in an m6A-dependent manner and underscores the importance of m6A mod-ification during CD8+T cell response.

Key words

CD8+T cell/T cell response/Mettl3/m6A/Effector/Memory

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基金项目

National Natural Science Foundation of China(32130039)

National Natural Science Foundation of China(31970831)

National Natural Science Foundation of China(81970541)

National Natural Science Foundation of China(31960151)

National Natural Science Foundation of China(31630038)

National Key Research and Development Program of China(2017YFA0104401)

Pinduoduo-China Agricultural University Research Fund(PC2023B01011)

Frontiers Science Center for Molecular Design Breeding(MOE)()

Chinese Universities Scientific Fund(2022TC030)

Chinese Universities Scientific Fund(2021TC087)

Project for Extramural Scientists of State Key Laboratory of Agrobiotechnology from China Agricultural University(2021SKLAB6-3)

Project for Extramural Scientists of State Key Laboratory of Agrobiotechnology from China Agricultural University(2021SKLAB6-4)

Collaborative Innovation Center of Chinese Ministry of Education(2020-39)

出版年

2024

科学通报(英文版)

中国科学院

科学通报(英文版)

CSTPCD

ISSN：1001-6538

参考文献量62

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