tRNA m1A modification is essential for gut homeostasis and function of group 3 innate lymphoid cells

Group 3 innate lymphoid cells (ILC3s) play crucial roles in maintaining intestinal homeostasis and defending against bacterial infections. However, the epigenetic mechanisms that regulate ILC3 responses are not well understood. In this study, we show that Trmt61a, the methyltransferase responsible for the m1A58 tRNA modification, is predominantly expressed in ILC3s. We found that specific depletion of TRMT61A in ILC3s leads to dysregulated cell cycle and a reduction in cell numbers. Notably, mice with an ILC3-specific TRMT61A deficiency exhibit dysbiosis, but antibiotic treatment can restore colonic ILC3 levels. Furthermore, these mice exhibit increased susceptibility to experimental intestinal inflammation and enteric bacterial infection. Our findings uncover a previously unrecognized role for TRMT61A mediated m1A modification in the regulation of intestinal ILC3s, essential for protecting intestinal tissue during inflammation and enhancing innate immunity against enteric pathogens. Overall design: To study the function of Trmt61a and tRNA m1A modification in ILC3 biology, we crossed Trmt61afl/fl mice with Rorccre mice to specifically delete Trmt61a expression in ILC3s. To explore the underlying molecular mechanism by which TRMT61A regulates ILC3 homeostasis, we isolated ILC3s from the intestines of Trmt61a?Rorc and Trmt61afl/fl mice and performed transcriptome sequencing.