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.
Highlights
Regulatory T cells (Treg cells) inhibit effector T cells and maintain immune system homeostasis
To understand how Treg cells can develop with such low levels of ongoing protein synthesis, we investigated the effects of TGFbeta and mTOR complex 1 (mTORC1) inhibition on the mechanism of canonical cap-dependent mTORC1/eIF4E mRNA translation initiation. mTORC1 signaling, shown by phosphorylation of mTORC1 targets P-S6 and P-4E-BP1, was most strongly blocked by RAD001 but not by TGF-beta treatment (Fig. 4e)
Discussion mTOR is a sensor of physiological stress and stimulatory signals in the tissue microenvironment, and a central gatekeeper of cellular metabolism. mTOR has emerged as a key regulator of T-cell function, plasticity and fate-determination[6,51], but its regulation of T-cell development and function through its effects on translational control are only beginning to be understood. mTOR activity has been shown to promote helper T-cell differentiation and determine Th1 or Th2 cell type through the selective activity of mTORC1 or mTORC217. mTOR promotes CD8+ effector T-cell development, in part by controlling the expression of two fate-determining transcription factors[52,53], through translationally controlled mechanisms[54]
Summary
Regulatory T cells (Treg cells) inhibit effector T cells and maintain immune system homeostasis. 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. Treg cells constitute ~5% of CD4+ T lymphocytes that exert antiproliferative action on activated immune cells They act by contact-dependent and independent mechanisms, thereby maintaining immune system homeostasis, inhibiting effector T cells in the periphery, controlling excessive responses to foreign antigens, and preventing autoimmune disease[1,2]. MTORC1 inhibition blocks cap-(m7G)-dependent mRNA translation, the major mechanism for protein synthesis, impairing protein synthesis just when pTreg cells need to differentiate and acquire immune-suppressing activity, which requires translation of mRNAs that specify these functions. A number of specialized translation mechanisms have been described that allow for selective mRNA translation, but which remain largely unexplored in immune cell development, including internal ribosome entry site (IRES)mediated mRNA translation and an alternate mechanism of capdependent but eIF4E/mTORC1-independent mRNA translation carried out by the DAP5/eIF3d complex[22]
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