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T cell responses

Quantity and quality control by mTOR

Nature Reviews Immunology volume 9, page 534 (2009)Cite this article

Delgoffe et al. generated mice with a conditional deletion of Frap1 (the gene encoding mTOR) in T cells. CD4+ T cells from these T-Frap1−/− mice failed to differentiate into T helper 1 (TH1), TH2 or TH17 effector cells in the presence of appropriate polarizing cytokines in vitro or in vivo. Despite expressing appropriate receptors for these polarizing cytokines, T-Frap1−/− CD4+ T cells had decreased phosphorylation of the downstream signal transducer and activator of transcription (STAT) factors in response to these cytokines and failed to upregulate lineage-specific transcription factors. Instead, the activation of T-Frap1−/− T cells resulted in the generation of a larger number of CD4+CD25+FOXP3+ regulatory T (TReg) cells compared with activation of wild-type T cells, and these FOXP3+ T cells had potent suppressive activity in vitro. T-Frap1−/− T cells had increased baseline levels of phosphorylation of SMAD3, which increased further with the addition of transforming growth factor-β (TGFβ).

These results indicate that mTOR controls the differentiation of effector versus regulatory CD4+ T cells in the periphery by regulating cytokine receptor signalling. In the absence of mTOR, the default pathway is the generation of TReg cells through hypersensitivity to TGFβ-induced SMAD3 phosphorylation and inhibition of STAT phosphorylation.

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References

ORIGINAL RESEARCH PAPERS

  1. Delgoffe, G. M. et al. The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. Immunity 30, 832–844 (2009)

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  2. Liu, G. et al. The receptor S1P1 overrides regulatory T cell-mediated immune suppression through Akt–mTOR. Nature Immunol. 10, 769–777 (2009)

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  3. Araki, K. et al. mTOR regulates memory CD8 T-cell differentiation. Nature 21 Jun 2009 (doi:10.1038/nature08155)

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FURTHER READING

  1. Thomson, A. W. et al. Immunoregulatory functions of mTOR inhibition. Nature Rev. Immunol. 9, 324–337 (2009)

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Authors
  1. Kirsty Minton
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Minton, K. Quantity and quality control by mTOR. Nat Rev Immunol 9, 534 (2009). https://doi.org/10.1038/nri2609

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