SLFN2 protection of tRNAs from stress-induced cleavage is essential for T cell–mediated immunity
Tao Yue, Xiaoming Zhan, Duanwu Zhang, Ruchi Jain, Kuan-Wen Wang, Jin Huk Choi, Takuma Misawa, Lijing Su, Jiexia Quan, Sara Hildebrand, Darui Xu, Xiaohong Li, Emre E. Turer, Lei Sun, Eva Marie Y. Moresco, Bruce Beutler
Abstract
Reactive oxygen species (ROS) increase in activated T cells because of metabolic activity induced to support T cell proliferation and differentiation. We show that these ROS trigger an oxidative stress response that leads to translation repression. This response is countered by Schlafen 2 (SLFN2), which directly binds transfer RNAs (tRNAs) to protect them from cleavage by the ribonuclease angiogenin. T cell-specific SLFN2 deficiency results in the accumulation of tRNA fragments, which inhibit translation and promote stress-granule formation. Interleukin-2 receptor β (IL-2Rβ) and IL-2Rγ fail to be translationally up-regulated after T cell receptor stimulation, rendering SLFN2-deficient T cells insensitive to interleukin-2's mitogenic effects. SLFN2 confers resistance against the ROS-mediated translation-inhibitory effects of oxidative stress normally induced by T cell activation, permitting the robust protein synthesis necessary for T cell expansion and immunity.