RNA m6A demethylase ALKBH5 regulates the development of γδ T cells

被引:24
|
作者
Ding, Chenbo [1 ,2 ]
Xu, Hao [3 ]
Yu, Zhibin [1 ,2 ]
Roulis, Manolis [3 ]
Qu, Rihao [3 ,4 ,5 ]
Zhou, Jing [1 ,2 ]
Oh, Joonseok [6 ,7 ]
Crawford, Jason [6 ,7 ,8 ]
Gao, Yimeng [9 ,10 ,11 ,12 ]
Jackson, Ruaidhri [3 ]
Sefik, Esen [3 ]
Li, Simiao [3 ]
Wei, Zheng [3 ]
Skadow, Mathias [3 ]
Yin, Zhinan [13 ,14 ]
Ouyang, Xinshou [15 ]
Wang, Lei [1 ]
Zou, Qiang [1 ]
Su, Bing [1 ,2 ]
Hu, Weiguo [1 ]
Flavell, Richard A. [3 ,16 ]
Li, Hua-Bing [1 ,2 ]
机构
[1] Shanghai Jiao Tong Univ, Shanghai Inst Immunol, Ruijin Hosp, Ctr Immune Related Dis,Sch Med,Dept Geriatr, Shanghai 200025, Peoples R China
[2] Shanghai Jiao Tong Univ, Yale Univ Inst Immune Metab, Sch Med, Shanghai 200025, Peoples R China
[3] Yale Univ, Sch Med, Dept Immunobiol, 333 Cedar St, New Haven, CT 06520 USA
[4] Yale Univ, Program Computat Biol & Bioinformat, New Haven, CT 06520 USA
[5] Yale Univ, Sch Med, Dept Pathol, New Haven, CT 06510 USA
[6] Yale Univ, Dept Chem, 225 Prospect St, New Haven, CT 06520 USA
[7] Yale Univ, Chem Biol Inst, West Haven, CT 06516 USA
[8] Yale Univ, Sch Med, Dept Microbial Pathogenesis, 333 Cedar St, New Haven, CT 06520 USA
[9] Yale Univ, Sch Med, Yale Canc Ctr, Sect Hematol, 333 Cedar St, New Haven, CT 06520 USA
[10] Yale Univ, Sch Med, Dept Internal Med, 333 Cedar St, New Haven, CT 06520 USA
[11] Yale Univ, Sch Med, Yale Stem Cell Ctr, 333 Cedar St, New Haven, CT 06520 USA
[12] Yale Univ, Sch Med, Yale RNA Ctr, 333 Cedar St, New Haven, CT 06520 USA
[13] Jinan Univ, Zhuhai Peoples Hosp, Zhuhai Precis Med Ctr, Zhuhai 519000, Guangdong, Peoples R China
[14] Jinan Univ, Fac Med Sci, Biomed Translat Res Inst, Guangzhou 510632, Guangdong, Peoples R China
[15] Yale Univ, Sch Med, Sect Digest Dis, Dept Internal Med, 333 Cedar St, New Haven, CT 06520 USA
[16] Yale Univ, Sch Med, HHMI, 333 Cedar St, New Haven, CT 06520 USA
基金
中国博士后科学基金; 中国国家自然科学基金;
关键词
RNA m(6)A modification; ALKBH5; gamma delta T cell development; Jagged1/Notch2; signaling; developmental checkpoint; ALPHA-BETA/GAMMA-DELTA; LINEAGE COMMITMENT; EXPRESSION; LIGAND; BETA; LCK; INACTIVATION; RESPONSES; THYMUS;
D O I
10.1073/pnas.2203318119
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
gamma delta T cells are an abundant T cell population at the mucosa and are important in providing immune surveillance as well as maintaining tissue homeostasis. However, despite gamma delta T cells' origin in the thymus, detailed mechanisms regulating gamma delta T cell development remain poorly understood. N-6-methyladenosine (m(6)A) represents one of the most common posttranscriptional modifications of messenger RNA (mRNA) in mammalian cells, but whether it plays a role in gamma delta T cell biology is still unclear. Here, we show that depletion of the m(6)A demethylase ALKBH5 in lymphocytes specifically induces an expansion of gamma delta T cells, which confers enhanced protection against gastrointestinal Salmonella typhimurium infection. Mechanistically, loss of ALKBH5 favors the development of gamma delta T cell precursors by increasing the abundance of m(6)A RNA modification in thymocytes, which further reduces the expression of several target genes including Notch signaling components Jagged1 and Notch2. As a result, impairment of Jagged1/Notch2 signaling contributes to enhanced proliferation and differentiation of gamma delta T cell precursors, leading to an expanded mature gamma delta T cell repertoire. Taken together, our results indicate a checkpoint role of ALKBH5 and m(6)A modification in the regulation of gamma delta T cell early development.
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页数:10
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