Regulation of translation initiation factor gene expression during human T cell activation

Activation of quiescent T cells leads to a dramatic increase in the rate of protein synthesis. It is believed that this pronounced increase of protein synthesis is regulated primarily at the level of translational initiation. Although considerable evidence demonstrates that translational initiation can be regulated at the post-translational level by the phosphorylation/dephosphorylation of translation initiation factors (eIFs) such as eIF-4E and eIF-2 alpha, additional mechanisms of eIF gene expression may also play a role in the regulation of translation in quiescent cells and/or during their subsequent induction to enter the cell cycle. To address this issue, gene expression of eIF-2 alpha, -4E, and -4A was studied in quiescent human peripheral blood T cells following stimulation through the T cell receptor-CD3 complex. Quiescent T cells expressed low levels of eIF-2 alpha, -4E, and -4A mRNAs and proteins as compared to proliferating T cells. Activation of resting T cells resulted in a rapid increase (20-50-fold) in the levels of these three mRNAs. This increase did not require new protein synthesis. Furthermore, transcription rates of these three eIF genes showed only minor increase over the induction period as measured by nuclear run-on assays. Despite the rapid increase in initiation factor mRNA levels, increases in eIF protein levels lagged significantly behind. Western blot analysis also showed that the protein levels of the three eIFs were differentially increased. eIF-4A protein levels increased in proportion to the observed increase in cellular protein synthetic activity while the increases in eIF-4E and eIF-2 alpha proteins were proportionately less. The low levels of eIF proteins in quiescent T cells appear to correlate with low protein synthesis rate in such cells. The induction of eIF proteins by post-transcriptional/translational mechanisms appears to contribute to the pronounced stimulation of protein synthesis that occurs during T cell activation.