Loss of the Transfer RNA Wobble Uridine-Modifying Enzyme Elp3 Delays T Cell Cycle Entry and Impairs T Follicular Helper Cell Responses through Deregulation of Atf4

J Immunol. 2021 Mar 1;206(5):1077-1087. doi: 10.4049/jimmunol.2000521. Epub 2021 Jan 22.


The activation of T cells is accompanied by intensive posttranscriptional remodeling of their proteome. We observed that protein expression of enzymes that modify wobble uridine in specific tRNAs, namely elongator subunit 3 (Elp3) and cytosolic thiouridylase (Ctu)2, increased in the course of T cell activation. To investigate the role of these tRNA epitranscriptomic modifiers in T cell biology, we generated mice deficient for Elp3 in T cells. We show that deletion of Elp3 has discrete effects on T cells. In vitro, Elp3-deficient naive CD4+ T cells polarize normally but are delayed in entering the first cell cycle following activation. In vivo, different models of immunization revealed that Elp3-deficient T cells display reduced expansion, resulting in functional impairment of T follicular helper (TFH) responses, but not of other CD4+ effector T cell responses. Transcriptomic analyses identified a progressive overactivation of the stress-responsive transcription factor Atf4 in Elp3-deficient T cells. Overexpression of Atf4 in wild-type T cells phenocopies the effect of Elp3 loss on T cell cycle entry and TFH cell responses. Reciprocally, partial silencing of Atf4 or deletion of its downstream effector transcription factor Chop rescues TFH responses of Elp3-deficient T cells. Together, our results reveal that specific epitranscriptomic tRNA modifications contribute to T cell cycle entry and promote optimal TFH responses.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 4 / genetics*
  • Activating Transcription Factor 4 / immunology
  • Animals
  • CD4-Positive T-Lymphocytes / immunology
  • Cell Cycle / genetics
  • Cell Cycle / immunology
  • Female
  • Histone Acetyltransferases / genetics*
  • Histone Acetyltransferases / immunology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • RNA Processing, Post-Transcriptional / genetics
  • RNA Processing, Post-Transcriptional / immunology
  • RNA, Transfer / genetics*
  • RNA, Transfer / immunology
  • T Follicular Helper Cells / immunology*
  • Transcriptome / genetics
  • Transcriptome / immunology
  • Uridine / genetics*
  • Uridine / immunology


  • Atf4 protein, mouse
  • Activating Transcription Factor 4
  • RNA, Transfer
  • Elp3 protein, mouse
  • Histone Acetyltransferases
  • Uridine