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

Science. 2021 May 14;372(6543):eaba4220. doi: 10.1126/science.aba4220.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Cell Proliferation
  • Female
  • Gene Deletion
  • Herpesviridae Infections / immunology
  • Immunity, Cellular*
  • Interleukin Receptor Common gamma Subunit / genetics
  • Interleukin Receptor Common gamma Subunit / metabolism
  • Interleukin-2 / metabolism
  • Interleukin-2 Receptor beta Subunit / genetics
  • Interleukin-2 Receptor beta Subunit / metabolism
  • Lymphocyte Activation
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Muromegalovirus
  • Oxidative Stress*
  • Protein Binding
  • Protein Biosynthesis
  • RNA, Transfer / metabolism*
  • Reactive Oxygen Species / metabolism
  • Receptors, Antigen, T-Cell / immunology
  • Receptors, Antigen, T-Cell / metabolism
  • Ribonuclease, Pancreatic / genetics
  • Ribonuclease, Pancreatic / metabolism
  • Signal Transduction
  • T-Lymphocytes / immunology*


  • Cell Cycle Proteins
  • Il2rb protein, mouse
  • Il2rg protein, mouse
  • Interleukin Receptor Common gamma Subunit
  • Interleukin-2
  • Interleukin-2 Receptor beta Subunit
  • Reactive Oxygen Species
  • Receptors, Antigen, T-Cell
  • schlafen-2 protein, mouse
  • RNA, Transfer
  • angiogenin
  • Ribonuclease, Pancreatic