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A DAP5/eIF3d alternate mRNA translation mechanism promotes differentiation and immune suppression by human regulatory T cells
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A DAP5/eIF3d alternate mRNA translation mechanism promotes differentiation and immune suppression by human regulatory T cells
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Journal Article
A DAP5/eIF3d alternate mRNA translation mechanism promotes differentiation and immune suppression by human regulatory T cells
2021
Overview
Regulatory 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.
The differentiation of naive T cells to immune suppressing induced regulatory T (iTreg) cells requires TGF-beta-1 and downregulation of mTORC1 activity, which inhibits mRNA translation. Here the authors show that iTreg cell differentiation uses an alternate mRNA translation mechanism involving translation factors DAP5 and eIF3d.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 13/109
/ 13/21
/ 13/31
/ 13/44
/ 13/51
/ 13/89
/ 38/39
/ 38/61
/ 38/91
/ Eukaryotic Initiation Factor-3 - genetics
/ Eukaryotic Initiation Factor-3 - metabolism
/ Eukaryotic Initiation Factor-4G - genetics
/ Eukaryotic Initiation Factor-4G - metabolism
/ Genomes
/ Homology
/ Humanities and Social Sciences
/ Humans
/ Kinases
/ Mechanistic Target of Rapamycin Complex 1 - metabolism
/ Proteins
/ Science
/ T-Lymphocytes, Regulatory - metabolism
