The RNA m6A reader YTHDF2 controls NK cell antitumor and antiviral immunity

Area of Science:

• Immunology
• Epigenetics
• Molecular Biology

Background:

• N6-methyladenosine (m6A) is the most abundant RNA modification.
• Natural killer (NK) cells are key innate immune cells for antiviral and antitumor responses.
• The role of m6A in NK cell immunity is largely unknown.

Purpose of the Study:

• To investigate the function of m6A modifications, specifically the reader YTHDF2, in NK cell immunity.
• To elucidate the mechanisms by which YTHDF2 impacts NK cell activity and homeostasis.

Main Methods:

• Studied YTHDF2 expression in activated NK cells.
• Utilized Ythdf2-deficient NK cells in vivo models of antitumor and antiviral immunity.
• Performed transcriptome-wide screening to identify YTHDF2 targets.
• Analyzed STAT5-YTHDF2 feedback loop in NK cell proliferation and survival.

Main Results:

• YTHDF2 is upregulated in activated NK cells.
• Ythdf2 deficiency impairs NK cell antitumor and antiviral functions.
• YTHDF2 is essential for NK cell homeostasis, terminal maturation, trafficking, and Eomes regulation.
• YTHDF2 promotes NK cell effector function and IL-15-mediated survival/proliferation via a STAT5-YTHDF2 feedback loop.
• Tardbp identified as a YTHDF2 target involved in NK cell proliferation/survival.

Conclusions:

• m6A modification via YTHDF2 plays a critical role in regulating NK cell immunity.
• YTHDF2 is a key regulator of NK cell homeostasis, maturation, and effector functions.
• Targeting YTHDF2 presents a potential strategy for enhancing NK cell-mediated antitumor immunity.