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

Naive T cells are quiescent but undergo dynamic changes upon antigenic activation. Li and colleagues show that upregulation of tRNA methyltransferase complex TRMT61A-TRMT6 and N-1-methyladenosine modification of tRNAs contribute to accelerated mRNA translation efficiency, in particular that of MYC protein, and are required for rapid T cell proliferation. 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) m(1)A58 'writer' proteins TRMT61A and TRMT6, which confer m(1)A58 RNA modification on a specific subset of early expressed tRNAs. These m(1)A-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-m(1)A58 modification in T cell-mediated pathogenesis and reveals a new mechanism of tRNA-m(1)A58-controlled T cell homeostasis and signal-dependent translational control of specific key proteins.

Automated summary

This study reveals the crucial roles of tRNA methylation and modification in promoting translation efficiency and rapid proliferation of T cells, shedding light on the pathogenesis and homeostasis of T cell-mediated diseases.