A DAP5/eIF3d alternate mRNA translation mechanism promotes differentiation and immune suppression by human regulatory T cells

• DOI: 10.1038/s41467-021-27087-w
• Publication Date: 2021-11-30T17:53:32Z
• Authors: Viviana Volta; Sandra Pérez-Baos; Columba de la Parra; Olga Katsara; Amanda Ernlund; Sophie Dornbaum; Robert J. Schneider
• Keywords: Immunosuppression Therapy; 0301 basic medicine; Science; Eukaryotic Initiation Factor-3; Q; Down-Regulation; Cell Differentiation; Mechanistic Target of Rapamycin Complex 1; Lymphocyte Activation; T-Lymphocytes, Regulatory; Article; Transforming Growth Factor beta1; 03 medical and health sciences; HEK293 Cells; Gene Expression Regulation; Protein Biosynthesis; Homeostasis; Humans; RNA, Messenger; Eukaryotic Initiation Factor-4G

AbstractRegulatory T cells (Treg cells) inhibit effector T cells and maintain immune system homeostasis. Treg cell maturation in peripheral sites requires inhibition of protein kinase mTORC1 and TGF-beta-1 (TGF-beta). While Treg cell maturation requires protein synthesis, mTORC1 inhibition downregulates it, leaving unanswered how Treg cells achieve essential mRNA translation for development and immune suppression activity. Using human CD4+ T cells differentiated in culture and genome-wide transcription and translation profiling, here we report that TGF-beta transcriptionally reprograms naive T cells to express Treg cell differentiation and immune suppression mRNAs, while mTORC1 inhibition impairs translation of T cell mRNAs but not those induced by TGF-beta. Rather than canonical mTORC1/eIF4E/eIF4G translation, Treg cell mRNAs utilize the eIF4G homolog DAP5 and initiation factor eIF3d in a non-canonical translation mechanism that requires cap-dependent binding by eIF3d directed by Treg cell mRNA 5’ noncoding regions. Silencing DAP5 in isolated human naive CD4+ T cells impairs their differentiation into Treg cells. Treg cell differentiation is mediated by mTORC1 downregulation and TGF-beta transcriptional reprogramming that establishes a DAP5/eIF3d-selective mechanism of mRNA translation.