Abstract
N6-methyladenosine (m6A), the most common and abundant epigenetic RNA modification, governs mRNA metabolism to determine cell differentiation, proliferation and response to stimulation. m6A methyltransferase METTL3 has been reported to control T cell homeostasis and sustain the suppressive function of regulatory T cells (Tregs). However, the role of m6A methyltransferase in other subtypes of T cells remains unknown. T helper cells 17 (Th17) play a pivotal role in host defense and autoimmunity. Here, we found that the loss of METTL3 in T cells caused serious defect of Th17 cell differentiation, and impeded the development of experimental autoimmune encephalomyelitis (EAE). We generated Mettl3f/fIl17aCre mice and observed that METTL3 deficiency in Th17 cells significantly suppressed the development of EAE and displayed less Th17 cell infiltration into central nervous system (CNS). Importantly, we demonstrated that depletion of METTL3 attenuated IL-17A and CCR5 expression by facilitating SOCS3 mRNA stability in Th17 cells, leading to disrupted Th17 cell differentiation and infiltration, and eventually attenuating the process of EAE. Collectively, our results highlight that m6A modification sustains Th17 cell function, which provides new insights into the regulatory network of Th17 cells, and also implies a potential therapeutic target for Th17 cell mediated autoimmune disease.
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Acknowledgements
This work was supported by the National Natural Science Foundation of China (82230067, 82061148013, 91842105, 81821001), Shanghai Science and Technology Committee (20JC1417400, 201409005500), the National Key Research and Development Program of China (2018YFA0508000), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB29030101), the CAS Project for Young Scientists in Basic Research (YSBR-074), and the Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment (2021B1212040004). We thank all other members of the Hua-Bing Li lab for discussions and comments.
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Wang, X., Chen, C., Sun, H. et al. m6A mRNA modification potentiates Th17 functions to inflame autoimmunity. Sci. China Life Sci. 66, 2543–2552 (2023). https://doi.org/10.1007/s11427-022-2323-4
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DOI: https://doi.org/10.1007/s11427-022-2323-4