Grant: Operating Grant

Foxp3+ regulatory T cells (Treg cells) are a subset of immunosuppressive lymphocytes that play central roles in the control of immune tolerance to self and non-self antigens. CD4+Foxp3+ Treg cells must integrate a spectrum of inflammatory, and other environmental stimuli to coordinate their action and orchestrate immune responses in vivo. Foxp3, a forkhead-winged helix transcriptional factor, is a master regulator of Treg cell genetic programming and lineage specification of Treg cells. Transcriptional and post-transcriptional mechanisms of gene regulation enable T cells to respond to inflammatory events, by altering the nature, amounts and activities of specific proteins required for their controlled and coordinated modulation of immunity. We found substantial changes in mRNA translation of specific mRNAs between CD4+ Treg and Teff cell subsets upon activation, and translationally regulated mRNAs are enriched for mRNAs encoding proteins involved in distinct biological processes. Specifically, we show that the mRNA encoding a pivotal translation initiation factor, eukaryotic translation initiation factor 4E (eIF4E), is translationally suppressed, accompanied by down-regulation of eIF4E protein levels, in activated Treg cells as compared to Teff cells. Strikingly, differential eIF4E induction between T-cell subsets correlate with translation of eIF4E-sensitive cell cycle related mRNAs, and modulate proliferation and Foxp3 expression. Thus, our preliminary data shows that distinct, translational programs differentially orchestrate fundamental cellular processes in CD4+ T cell subsets: the eIF4E mRNA, is translationally suppressed in activated Foxp3+ Treg cells, and imprints these cells with a Treg-specific translational gene signature involved in lineage indentity and stability of function. We will investigate the molecular pathways that regulate eIF4E-dependent, translational control of gene expression in Foxp3+ Treg cells in mouse models of inflammation.