Distinct Translational Control in CD4+ T Cell Subsets

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 (T_Foxp3+) and CD4⁺Foxp3⁻ non-regulatory T (T_Foxp3−) 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 T_Foxp3− and T_Foxp3+ 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. Regulatory T cells expressing the nuclear protein Foxp3 are essential for the control of immune responses towards self and foreign antigens. Genome-wide gene expression studies have defined canonical signatures of T cell subsets. However, 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 Foxp3⁻ T cells and establishes proteomes and functions in T cell subsets. We also show that cell activation or growth factors increase the translation of eukaryotic translation initiation factor 4E (eIF4E), which induces proliferation in both T cell subsets. Unexpectedly, eIF4E also affects Foxp3 expression and can drive lineage identity. Thus, distinct translational control directs both common and distinct cellular processes in CD4⁺ T cell subsets.