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

Using genetic mouse models, high-throughput sequencing, transcriptome-wide m1A profiling and ribosome profiling, we find: (1) Translation is the most active process of these genetic information processing in early T cell activation. (2) T cells upregulate tRNA-m1A58 “writer” proteins TRMT61A and TRMT6 to install m1A58 modification to a specific subset of early expressed tRNAs during the early stage of activation. (3) m1A58 modifications in tRNA support rapid and adequate synthesis of MYC and other key functional proteins, guide the exit of naïve T cells from quiescence state into a proliferative state, and promote rapid T cell expansion after activation. Overall design: For RNA-seq, there are 0h,3h,6h,18h,48h for WT samples and 0h,3h,6h,48h for Trmt61A-cKO samples. For m1A-seq,there are 6h WT/cKO samples. For tRNA-seq, naïve CD4+ T cells were isolated from WT mice and activated with plate-bound anti-CD3 plus anti-CD28 in a 96-well plate for 0,6,18,48 hours. For RiboTag-seq, 500 million naïve CD4+ T cells were isolated from WT (RiboTagflox/floxCd4Cre) and Trmt61a-KO (Trmt61aflox/floxRiboTagflox/floxCd4Cre) mice (activated with plate-bound anti-CD3 plus anti-CD28 in 96-well plate for 6 hours).