m6A RNA modification guides alternative polyadenylation to maintain T cell quiescence.

N6-Methyladenosine (m6A) is primarily enriched in the last exons and 3' untranslated regions (3'UTRs) of messenger RNAs (mRNAs) and is associated with T cell homeostasis. Upon T cell activation, global mRNA 3'UTR shortening is facilitated through alternative polyadenylation (APA). However, it is unclear how T cells coordinate these two important posttranscriptional regulatory events to maintain quiescence. Here, we found that the m6A "writer" METTL3 directly interacts with APA factor NUDT21 and guided poly(A) site selection. Deletion of Nudt21 in T cells resulted in simultaneous overactivation and accelerated apoptosis, leading to T cell loss and impaired adaptive immune function. Mechanistically, METTL3 recruits NUDT21 to the proximal poly(A) site of Rragd mRNA, generating long 3'UTR with m6A modifications. Nudt21 deficiency causes Rragd 3'UTR shortening and increases Rragd expression, leading to overactivation of mammalian target of rapamycin signaling. Our study reveals an m6A-guided poly(A) site selection mechanism and defines in vivo roles of m6A-APA cross-talk in maintaining T cell quiescence.