Distinct Translational Control in CD4+ T Cell Subsets

Eva Bjur,Shui Li,Carston R Wagner,Ivan Topisirovic,Ciriaco A Piccirillo,Ola Larsson,Lei Zheng,Valentina Gandin,Ekaterina Yurchenko,Nahum Sonenberg,Derry C Roopenian

doi:10.1371/journal.pgen.1003494

Abstract

Regulatory T cells expressing the transcription factor Foxp3 play indispensable roles for the induction and maintenance of immunological self-tolerance and immune homeostasis. Genome-wide mRNA expression studies have defined canonical signatures of T cell subsets. Changes in steady-state mRNA levels, however, often do not reflect those of corresponding proteins due to post-transcriptional mechanisms including mRNA translation. Here, we unveil a unique translational signature, contrasting CD4+Foxp3+ regulatory T (TFoxp3+) and CD4+Foxp3− non-regulatory T (TFoxp3−) cells, which imprints subset-specific protein expression. We further show that translation of eukaryotic translation initiation factor 4E (eIF4E) is induced during T cell activation and, in turn, regulates translation of cell cycle related mRNAs and proliferation in both TFoxp3− and TFoxp3+ cells. Unexpectedly, eIF4E also affects Foxp3 expression and thereby lineage identity. Thus, mRNA–specific translational control directs both common and distinct cellular processes in CD4+ T cell subsets.

Highlights

Regulation of gene expression is a multi-step process involving transcriptional, post-transcriptional and post-translational mechanisms
Changes in mRNA levels often do not reflect those of corresponding proteins due to post-transcriptional mechanisms including mRNA translation
In Bjur et al, we discovered a unique translational signature, which distinguishes immunosuppressive Foxp3+ regulatory T from inflammatory Foxp32 T cells and establishes proteomes and functions in T cell subsets

Summary

Introduction

Regulation of gene expression is a multi-step process involving transcriptional, post-transcriptional and post-translational mechanisms. Several studies have documented that changes in steady-state mRNA expression-profiles frequently do not correspond to changes in the proteome [3,4,5,6]. CD4+ T helper (Th)-cell lineage differentiation is defined by expression of specific transcription factors required for subset identity [7]. Genome-wide expression profiles using steady-state mRNA samples have defined canonical ‘‘TFoxp3+ gene expression signatures’’ that distinguish primary resting or activated TFoxp3+ from CD4+Foxp non-regulatory T (TFoxp32) cells [11,12,13,14,15]. Studies of mRNA translation in T cells are limited but suggest that T cells augment mRNAtranslation and induce translation of specific mRNAs upon activation [16,17,18]. We asked whether translational control contributes to establishment of the proteomes in TFoxp3+ and/or TFoxp cells

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Discussion

Conclusion