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Abstract
Abstract Maturation of regulatory T cells (Tregs) in peripheral sites is known to require TGFβ exposure and inhibition of protein kinase mTORC1. It is well known that mTOR inhibition is associated with repression of cap-dependent mRNA translation, which represents the major mechanism for protein synthesis, leaving unanswered how Tregs carry-out essential translation for development and immune suppression activity. To answer this question, we performed genome-wide transcription and translation profiling in CD4+CD127dim/− CD25+Tregs derived from anti-CD3/CD28-activated human naïve CD4+ T cells, treated with the mTORC1 inhibitor RAD001 and/or TGFβ. We found that TGFβ activated both Treg differentiation and immune suppression genes, while mTORC1 inhibition selectively blocked translation of most T cell mRNAs except those induced by TGFβ, including FOXP3, CTLA-4, CD101 or CD103, locking in Treg lineage commitment and immune suppression function. These canonical Treg fate-determining mRNAs were resistant to mTORC1 inhibition, an effect mediated in part by their 5′-untranslated regions through an alternate form of appears to be cap-dependent, eIF4E-independent mRNA translation. In conclusion, TGFβ transcriptional reprogramming together with mTORC1-independent translational reprogramming enable a privileged translation mechanism by which activated CD4+ T cells become Tregs.
Published Version
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