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
- 1 March 2021
- journal article
- research article
- Published by The American Association of Immunologists in The Journal of Immunology
- Vol. 206 (5), 1077-1087
- https://doi.org/10.4049/jimmunol.2000521
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.Keywords
Funding Information
- Fonds de la Recherche Scientifique, National Fund for Scientific Research (J00641F, CR-2015S-01, Research Associate, Research Director)
- Fonds pour la Formation à la Recherche dans l’Industrie et dans l’Agriculture, National Fund for Scientific Research
- Léon Frédéricq Foundation of the University of Liege
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