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

Author

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  • Viviana Volta

    (Synthis LLC, 430 East 29th Street, Launch Labs, Alexandria Center for Life Sciences)

  • Sandra Pérez-Baos

    (NYU Grossman School of Medicine)

  • Columba Parra

    (City University of New York)

  • Olga Katsara

    (NYU Grossman School of Medicine)

  • Amanda Ernlund

    (Johns Hopkins Applied Physics Lab)

  • Sophie Dornbaum

    (NYU Grossman School of Medicine)

  • Robert J. Schneider

    (NYU Grossman School of Medicine
    Perlmutter Cancer Center, NYU Grossman School of Medicine
    Colton Center for Autoimmunity, NYU Grossman School of Medicine)

Abstract

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.

Suggested Citation

  • Viviana Volta & Sandra Pérez-Baos & Columba Parra & Olga Katsara & Amanda Ernlund & Sophie Dornbaum & Robert J. Schneider, 2021. "A DAP5/eIF3d alternate mRNA translation mechanism promotes differentiation and immune suppression by human regulatory T cells," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-27087-w
    DOI: 10.1038/s41467-021-27087-w
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    References listed on IDEAS

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    1. Mykola Roiuk & Marilena Neff & Aurelio A. Teleman, 2024. "eIF4E-independent translation is largely eIF3d-dependent," Nature Communications, Nature, vol. 15(1), pages 1-17, December.

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