Key Points
tRNA wobble uridine–modifying enzymes promote T cell cycle entry and TFH responses.
Wobble uridine modifications regulate Atf4 signaling in activated T cells.
Overactivated Atf4 delays Elp3-deficient T cell cycle entry and impairs TFH responses.
Abstract
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.
Footnotes
↵1 P.L., Q.B., and C.L. are equal contributors.
This work was supported by the Fonds de la Recherche Scientifique, National Fund for Scientific Research (Credit de Recherche Grant J00641F and Walloon Excellence in Life Sciences and Biotechnology FRFS-WELBIO Grant CR-2015S-01), the Fonds pour la Formation à la Recherche dans l’Industrie et dans l’Agriculture, National Fund for Scientific Research (to P.L. and C.L.), the Léon Frédéricq Foundation of the University of Liege, and the University of Liege (Action de Recherche Concertee: tRAME). Funders took no part in data collection, analysis, or manuscript preparation.
The RNA sequencing data presented in this article have been submitted to ArrayExpress database (https://www.ebi.ac.uk/arrayexpress) under accession numbers E-MTAB-9057 and E-MTAB-9059.
The online version of this article contains supplemental material.
- Received May 7, 2020.
- Accepted December 19, 2020.
- Copyright © 2021 by The American Association of Immunologists, Inc.
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