The kinase mTOR regulates the differentiation of helper T cells through the selective activation of signaling by mTORC1 and mTORC2

Abstract

The kinase mTOR has emerged as an important regulator of the differentiation of helper T cells. Here we demonstrate that differentiation into the TH1 and TH17 subsets of helper T cells was selectively regulated by signaling from mTOR complex 1 (mTORC1) that was dependent on the small GTPase Rheb. Rheb-deficient T cells failed to generate TH1 and TH17 responses in vitro and in vivo and did not induce classical experimental autoimmune encephalomyelitis (EAE). However, they retained their ability to become TH2 cells. Alternatively, when mTORC2 signaling was deleted from T cells, they failed to generate TH2 cells in vitro and in vivo but preserved their ability to become TH1 and TH17 cells. Our data identify mechanisms by which two distinct signaling pathways downstream of mTOR regulate helper cell fate in different ways. These findings define a previously unknown paradigm that links T cell differentiation with selective metabolic signaling pathways.

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Figure 1: Rheb controls mTORC1 activity in T cells.
Figure 2: TH1 and TH17 differentiation require mTORC1 in vitro, but mTORC1 is dispensable for TH2 differentiation.
Figure 3: T cells deficient in mTORC1 cannot skew toward TH1 or TH17 in vivo.
Figure 4: T-Rheb−/− mice do not develop EAE but instead develop an alternative autoimmune disease.
Figure 5: T cells deficient in mTORC2 cannot skew toward TH2 but retain TH1 and TH17 skewing.
Figure 6: Both mTORC1 and mTORC2 influence cytokine signaling by inhibiting SOCS proteins differently.
Figure 7: Control of the induction of transcription factors by mTORC1 and mTORC2.
Figure 8: Inhibition of both mTORC1 and mTORC2 is required for spontaneous induction of Treg cells.

Change history

  • 06 May 2011

    In the version of this article initially published, the Discussion section cited a published study of mice with conditional deletion of Rictor in T cells without specifying which Lck promoter was used to drive the expression of Cre recombinase. The distal Lck promoter (dLck) was used. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank P.F. Worley (Johns Hopkins University) for mice with loxP-flanked Rheb alleles; M. Magnuson (Vanderbilt University) for mice with loxP-flanked Rictor alleles; S.C. Kozma (University of Cincinnati) for mice with loxP-flanked Mtor alleles; C. Drake (Johns Hopkins University) for vaccinia virus expressing ovalbumin; members of the Powell laboratory; and C. Drake and D. Pardoll for discussions and reagents. Supported by the US National Institutes of Health (R01AI077610-01A2).

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Contributions

G.M.D. did research, helped design experiments and wrote the paper; K.N.P. assisted with in vivo experiments and biochemistry; A.T.W. assisted with EAE induction and central nervous system isolation and did immunohistochemistry; E.H. assisted with very-low-dose rapamycin experiments; D.J.M. synthesized the mTOR kinase inhibitor; M.R.H. helped design experiments and contributed reagents; B.X. and P.F.W. generated the original mouse line with loxP-flanked Rheb alleles; and J.D.P. designed experiments, oversaw research and wrote the paper.

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Correspondence to Jonathan D Powell.

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The authors declare no competing financial interests.

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Supplementary Text and Figures

Supplementary Figures 1–13 (PDF 9152 kb)

41590_2011_BFni2005_MOESM6_ESM.mov

Rheb-deficient T cells induce nonclassical EAE. Video of a representative T-Rheb−/− mouse 14 days after immunization with MOG peptide + CFA to induce EAE. The mouse displays symptoms of ataxia without paralysis. (MOV 5111 kb)

Supplementary Video 1

Rheb-deficient T cells induce nonclassical EAE. Video of a representative T-Rheb−/− mouse 14 days after immunization with MOG peptide + CFA to induce EAE. The mouse displays symptoms of ataxia without paralysis. (MOV 5111 kb)

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Delgoffe, G., Pollizzi, K., Waickman, A. et al. The kinase mTOR regulates the differentiation of helper T cells through the selective activation of signaling by mTORC1 and mTORC2. Nat Immunol 12, 295–303 (2011). https://doi.org/10.1038/ni.2005

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