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

Nat Commun. 2021 Nov 30;12(1):6979. doi: 10.1038/s41467-021-27087-w.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Differentiation*
  • Down-Regulation
  • Eukaryotic Initiation Factor-3 / genetics
  • Eukaryotic Initiation Factor-3 / metabolism*
  • Eukaryotic Initiation Factor-4G / genetics
  • Eukaryotic Initiation Factor-4G / metabolism*
  • Gene Expression Regulation
  • HEK293 Cells
  • Homeostasis
  • Humans
  • Immunosuppression Therapy*
  • Lymphocyte Activation
  • Mechanistic Target of Rapamycin Complex 1 / metabolism
  • Protein Biosynthesis*
  • RNA, Messenger
  • T-Lymphocytes, Regulatory / metabolism*
  • Transforming Growth Factor beta1 / metabolism


  • EIF3D protein, human
  • EIF4G2 protein, human
  • Eukaryotic Initiation Factor-3
  • Eukaryotic Initiation Factor-4G
  • RNA, Messenger
  • TGFB1 protein, human
  • Transforming Growth Factor beta1
  • Mechanistic Target of Rapamycin Complex 1