SLFN2 protection of tRNAs from stress-induced cleavage is essential for T cell-mediated immunity

During T cell mediated immune response, metabolic reprograming is required for energy production to support the following clonal expansion, and leading to increased levels of reactive oxygen species. Proper responses to such oxidative stress in activated T cells have been shown to be extremely important in mediating T cell proliferation. Here we report Schlafen (SLFN) 2, upregulated upon the stimulation of T cell antigen receptor (TCR), directly binds to tRNAs and maintains their integrity against stress-activated cleavage. T-cell specific inactivation of Slfn2 in mice leads to compromised humoral and cellular immune responses in mice. Mechanistically, loss of Slfn2 in activated T cells causes significantly enhanced tRNA fragmentation, stress granule assembly and protein synthesis inhibition, which impairs activation-induced T cell proliferation by failing to upregulate protein synthesis and conferring IL-2 insensitivity. Thus, SLFN2 is a novel trans-acting factor for tRNA integrity and crucial to T cell-mediated immunity. RNAs isolated from each of indicated groups by using miRNA Isolation Kit, were demethylated for subsequent cDNA library preparation using TruSeq Small RNA Library Prep kit. Each cDNA library containing tRNA-derived fragments with index was size-selected on 8% TBE-PAGE gel to isolate cDNAs. Individual purified tRNA-derived framgent libraries were pooled and sequenced by using the NSQ 500/550.