Translational regulation directs fate decisions involved in memory CD8 T cell differentiation

Abstract

Abstract mTOR regulates the formation of memory CD8 T cells that circulate in the blood and are present in lymphoid organs. These memory CD8 T cells are the basis for long-lived T cell immunity and efficiently control re-infection to the previously encountered pathogens. Here, we show that the fate decisions between memory precursor and terminal effector CD8 T cells are regulated by the cap-dependent translation that is the downstream pathway of mTOR. Experiments using RNA interference to inhibit expression of eIF4E, which is a cap-binding protein and a translation initiation factor, in antigen-specific CD8 T cells revealed that high eIF4E expression induced terminal effector cells and low expression promoted memory precursor cells. This eIF4E dependent regulation of memory CD8 T cell differentiation was also confirmed by the overexpression of a constitutively active form of 4E-BP that inhibits cap-dependent translation by binding to eIF4E. RNA immunoprecipitation analysis with anti-eIF4E antibody between naïve and activated CD8 T cells showed that, rather than all mRNAs, the interaction of specific groups of mRNAs (i.e., translation and oxidative phosphorylation) with eIF4E was dynamically regulated during activation of the T cells. Transcripts related to translation and oxidative phosphorylation inefficiently bound to eIF4E in naïve CD8 T cells but the level of competence of these transcripts in binding to eIF4E was significantly improved in activated CD8 T cells. Thus, our data show that eIF4E-dependent translation is actively and selectively regulated during naïve to effector CD8 T cell differentiation and has an important role in fate decisions involved in the formation of memory CD8 T cells.