SLFN2 protection of tRNAs from stress-induced cleavage is essential for T cell‚Äìmediated immunity
Authors: Jin Huk Choi
Eva Marie Y Moresco
Emre Turer
Duanwu Zhang
Kuan-Wen Wang
Lijing Su
Ruchi Jain
Takuma Misawa
Xiaohong Li
Bruce Beutler
Tao Yue
Sara Hildebrand
Darui Xu
Xiaoming Zhan
Jiexia Quan
Lei Sun
Journal: Science (2021)
Discipline: Multidisciplinary
Keywords: Reactive oxygen species; T cells; translation repression; Schlafen 2; tRNAs
Affiliations: Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

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 Œ≤ (IL-2RŒ≤) and IL-2RŒ≥ 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. 

Retracted: No

PubPeer comments:
 Dear authors, We have with great interest and excitement discussed your paper u201cSLFN2 protection of tRNAs from stress-induced cleavage is essential for T-cell mediated immunityu201d during our weekly literature meeting. Your paper is an impressive and rare example of a fully covered investigation of a proteinu2019s function - from the phenotype to the molecular mechanism. Metabolic reprogramming and induced translation in activated T-cells are still uncharted territories, which require further research (such as yours). Moreover, SLFN2 and its mechanism of function constitute an interesting potential target for immunotherapies. However, after reading your paper, we were left wondering about a few things that we think would be interesting to see explored or commented on, either here, or in future publications: 1. You found that SLFN2 affects transcripts of IL2Rbeta and gamma, but not alpha. It would be interesting to find other targets affected by SLFN2 KO to figure out the common denominator. You explained the selective effect with the relative abundance of the given transcript. Might it be that the mechanism is more specific? Could SLFN2 target only specific tRNAs, for example, tRNAs which are more prone to angiogenin cleavage, and at the same time necessary for the translation of only specific transcripts? 2. Is angiogenin competing with SLFN2 for tRNA? Or is it a matter of ANG:SLFN2:tRNA ratio? Or do the proteins act upstream downstream of each other? You found that SLFN2 expression is induced upon TCR stimulation. What about angiogenin expression? 3. What is your hypothesis for how SLFN2 is regulated? Is it more active in specific T cell subsets or in other hematopoietic cells? 4. Angiogenin knockdown does not rescue the phenotype fully. Is it possible that the mechanism described in your paper is more general and applies to other RNases (tRNA cleaving enzymes) as well? 5. We noticed that some of your experiments were performed with cells pooled from a few mice. Was the number of cells collected from different mice similar? There might be a risk of getting skewed results due to dominating phenotypes or uneven number of cells. Would it not be more robust (in terms of statistics) to treat each mouse as a separate biological sample? We would greatly appreciate if you could share your thoughts on our comments above, as this may aid us (and other readers) in better understanding your work and thus help us all contribute to a fruitful scientific discussion. ,