Title: tRNA-m¹A modification promotes T cell expansion via efficient MYC protein synthesis

Abstract: Naive T cells undergo radical changes during the transition from dormant to hyperactive states upon activation, which necessitates de novo protein production via transcription and translation. However, the mechanism whereby T cells globally promote translation remains largely unknown. Here, we show that on exit from quiescence, T cells upregulate transfer RNA (tRNA) m¹A58 ‘writer’ proteins TRMT61A and TRMT6, which confer m¹A58 RNA modification on a specific subset of early expressed tRNAs. These m¹A-modified early tRNAs enhance translation efficiency, enabling rapid and necessary synthesis of MYC and of a specific group of key functional proteins. The MYC protein then guides the exit of naive T cells from a quiescent state into a proliferative state and promotes rapid T cell expansion after activation. Conditional deletion of the Trmt61a gene in mouse CD4⁺ T cells causes MYC protein deficiency and cell cycle arrest, disrupts T cell expansion upon cognate antigen stimulation and alleviates colitis in a mouse adoptive transfer colitis model. Our study elucidates for the first time, to our knowledge, the in vivo physiological roles of tRNA-m¹A58 modification in T cell-mediated pathogenesis and reveals a new mechanism of tRNA-m¹A58-controlled T cell homeostasis and signal-dependent translational control of specific key proteins.