N6-methyladenosine (m6A) is the most prevalent posttranscriptional modification on RNA. NK cells are the predominant innate lymphoid cells that mediate antiviral and antitumor immunity. However, whether and how m6A modifications affect NK cell immunity remain unknown. Here, we discover that YTHDF2, a well-known m6A reader, is upregulated in NK cells upon activation by cytokines, tumors, and cytomegalovirus infection. Ythdf2 deficiency in NK cells impairs NK cell antitumor and antiviral activity in vivo. YTHDF2 maintains NK cell homeostasis and terminal maturation, correlating with modulating NK cell trafficking and regulating Eomes, respectively. YTHDF2 promotes NK cell effector function and is required for IL-15–mediated NK cell survival and proliferation by forming a STAT5–YTHDF2 positive feedback loop. Transcriptome-wide screening identifies Tardbp to be involved in cell proliferation or survival as a YTHDF2-binding target in NK cells. Collectively, we elucidate the biological roles of m6A modifications in NK cells and highlight a new direction to harness NK cell antitumor immunity.
The RNA m6A reader YTHDF2 controls NK cell antitumor and antiviral immunity
Disclosures: J. Chen reported "other" from Genovel Biotech Corp. outside the submitted work and is a scientific founder of Genovel Biotech Corp. and a scientific advisor of race oncology. No other disclosures were reported.
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Shoubao Ma, Jiazhuo Yan, Tasha Barr, Jianying Zhang, Zhenhua Chen, Li-Shu Wang, Joseph C. Sun, Jianjun Chen, Michael A. Caligiuri, Jianhua Yu; The RNA m6A reader YTHDF2 controls NK cell antitumor and antiviral immunity. J Exp Med 2 August 2021; 218 (8): e20210279. doi: https://doi.org/10.1084/jem.20210279
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