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 Turer; Lei Sun; Eva Marie Y Moresco; Bruce Beutler

doi:10.1126/science.aba4220

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.

Authors

Tao Yue¹, Xiaoming Zhan¹, Duanwu Zhang¹, Ruchi Jain¹, Kuan-Wen Wang¹, Jin Huk Choi¹, Takuma Misawa¹, Lijing Su¹, Jiexia Quan¹, Sara Hildebrand¹, Darui Xu¹, Xiaohong Li¹, Emre Turer^{1

2}, Lei Sun¹, Eva Marie Y Moresco¹, Bruce Beutler³

Affiliations

¹ Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
² Department of Internal Medicine, Division of Gastroenterology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
³ Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. [email protected].

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.

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*

Substances

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

Abstract

Publication types

MeSH terms

Substances

Grants and funding