Regulatory T cells (Tregs) suppress the activation and subsequent effector functions of CD4 effector T cells (Teffs). However, molecular mechanisms that enforce Treg-mediated suppression in CD4 Teff are unclear. We found that Tregs suppressed activation-induced global protein synthesis in CD4 Teffs prior to cell division. We analyzed genome-wide changes in the transcriptome and translatome of activated CD4 Teffs. We show that mRNAs encoding for the protein synthesis machinery are regulated at the level of translation in activated CD4 Teffs by Tregs. Tregs suppressed global protein synthesis of CD4 Teffs by specifically inhibiting mRNAs of the translation machinery at the level of mTORC1-mediated translation control through concerted action of immunosuppressive cytokines IL-10 and TGFβ. Lastly, we found that the therapeutic targeting of protein synthesis with the RNA helicase eIF4A inhibitor rocaglamide A can alleviate inflammatory CD4 Teff activation caused by acute Treg depletion in vivo. These data show that peripheral tolerance is enforced by Tregs through mRNA translational control in CD4 Teffs.
Regulatory T cells suppress CD4+ effector T cell activation by controlling protein synthesis
Disclosures: V.S. Muir reported “other” from Janssen R&D outside the submitted work. J.H. Buckner reported “other” from Gentibio and grants from Helmsley Charitable Trust outside the submitted work; in addition, J.H. Buckner had a patent to PCT/US2020/039445 pending and a patent to US 8,053,235 issued and is a Scientific Co-Founder and Scientific Advisory Board member of GentiBio, a company engaged in developing engineered regulatory T cell therapies. No other disclosures were reported.
L. So’s current affiliation is Kumquat Biosciences, San Diego, CA, USA.
- Award Id(s): R21AI143227,5T32AI106677-07 (T32),1F32AI145283-01A1 (F32)
Lomon So, Kazushige Obata-Ninomiya, Alex Hu, Virginia S. Muir, Ayako Takamori, Jing Song, Jane H. Buckner, Ram Savan, Steven F. Ziegler; Regulatory T cells suppress CD4+ effector T cell activation by controlling protein synthesis. J Exp Med 6 March 2023; 220 (3): e20221676. doi: https://doi.org/10.1084/jem.20221676
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