Jurgens, A. P.; Zwijnen, J.; Van Alphen, F. P. J.; Bradaric, A.; Rooijers, K.; Hoogendijk, A. J.; Popovic, B.; Wolkers, M. C.

T cells are key contributors to clear our body from infected and malignant cells. When T cells respond to target cells, they undergo profound translational alterations. The evolutionary and highly conserved kinase mammalian target of rapamycin (mTOR) is a central mediator of T cell differentiation, homeostasis, and T cell activation, including the production of the key pro-inflammatory cytokines TNF, IL2, and IFNy;. mTOR was shown to execute its translation activity through TOP motifs located in the 5 Untranslated region (5UTR) of its target genes. Here, we uncovered a distinct mechanism of mTOR signaling on cytokine production in T cells, which is under control of the 3UTR. Even though non-classical TOP motifs are present in cytokine 3UTRs, they 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 3UTR AREs and confers the mTOR-mediated translation control. In conclusion, we here present a previously unappreciated ARE-dependent, 3UTR-mediated mode of action that mTOR employs to regulate cytokine production.