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 (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.

Post-Transcriptional and Translational Mechanisms of Regulation of Gene Expression in T Cell Subsets

“…Consistent with the translational silencing of eIF4E in T REG cells, mTOR gene deficiency or inhibition can abrogate the proliferation and differentiation of Th1, Th2, or Th17 cells, while promoting Foxp3 expression and adopting a T REG phenotype [122]. In line with this, inhibition of eIF4E activity in CD4+ T cells abrogated their proliferation in response to TCR stimulation in the presence of IL-2 [120]. Surprisingly, inhibition of eIF4E activity in activated T EFF cells also resulted in the induction of Foxp3 expression in a subset of cells, suggesting that modulation of eIF4E expression may impact CD4+ T cell lineage identity, with translational silencing of eIF4E being required for T REG stability.…”

“…Additionally, the rate of GATA3 translation is increased following the activation of the CD28 co-stimulatory pathway in CD4+ T cells without direct increase in GATA3 mRNA abundance, while IL-4 signaling can facilitate IL-4 translation in a similar manner [97,119]. Recently, a genome-wide study examined the role of mRNA translational regulation in CD4+ T cell subsets [120]. The isolation of polyribosome-bound transcripts, enriched with highly translated mRNA transcripts and comparison with total cytosolic mRNA, identified distinct translational signatures differentiating T REG and T EFF cells.…”

Inhibiting CARD11 translation during BCR activation by targeting the eIF4A RNA helicase

“…This observation is consistent with previous studies demonstrating increased eIF4E protein expression on lymphocyte activation. 36 Together, these data demonstrate that eIF4A capbinding activity and p70s6K signaling is rapidly enhanced on BCR activation.…”

IL-15 activates mTOR and primes stress-activated gene expression leading to prolonged antitumor capacity of NK cells

“…Recently, studies of "translatomes" (ie, the pool of translated messenger RNAs [mRNAs]) using polysome or ribosome profiling have highlighted mRNA translation as a key mechanism controlling gene expression and influencing a wide range of functions in immune cells. [11][12][13] Changes in translational efficiency affect protein levels without changes in steady-state mRNA levels, thereby enabling rapid adaptation to environmental changes essential for a functional immune system. 13 Thus, profiling mRNA translation may be essential to efficiently link observed immune cell phenotypes to underlying gene expression programs.…”