mTOR signaling during T cell activation promotes cytokine production in T cells through 3′ UTR-mediated translation control

T cells are key contributors to clearing our body of infected and malignant cells. During activation, T cells undergo profound translational alterations, and the evolutionarily and highly conserved kinase mammalian target of rapamycin (mTOR) is central in this process. It mediates T cell differentiation, homeostasis, and activation and promotes the production of pro-inflammatory cytokines. mTOR executes its translation activity through terminal oligopyrimidine (TOP) motifs located in the 5′ untranslated region (5′ UTR) of target genes. Here, we uncovered a distinct 3′ UTR-mediated mechanism of mTOR signaling on cytokine production in T cells. Non-classical TOP motifs present in the cytokine 3′ UTRs do not contribute to mTOR-mediated translation regulation. Rather, AU-rich elements (AREs) are required for mTOR-mediated cytokine production. Furthermore, we discovered that the RNA-binding protein DDX21 binds to 3′ UTR AREs and confers mTOR-mediated translation control. In conclusion, we present a previously unappreciated ARE-dependent, 3′ UTR-mediated mechanism that mTOR employs to regulate cytokine production.