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

Nature Immunology volume 12, pages 295–303 (2011)Cite this article

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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.

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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.

References

  1. Guertin, D.A. & Sabatini, D.M. Defining the role of mTOR in cancer. Cancer Cell 12, 9–22 (2007).

    Article  CAS  Google Scholar 

  2. Hay, N. & Sonenberg, N. Upstream and downstream of mTOR. Genes Dev. 18, 1926–1945 (2004).

    Article  CAS  Google Scholar 

  3. Kim, D.H. et al. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 110, 163–175 (2002).

    Article  CAS  Google Scholar 

  4. Sarbassov, D.D. et al. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr. Biol. 14, 1296–1302 (2004).

    Article  CAS  Google Scholar 

  5. Laplante, M. & Sabatini, D.M. mTOR signaling at a glance. J. Cell Sci. 122, 3589–3594 (2009).

    Article  CAS  Google Scholar 

  6. Holz, M.K. & Blenis, J. Identification of S6 kinase 1 as a novel mammalian target of rapamycin (mTOR)-phosphorylating kinase. J. Biol. Chem. 280, 26089–26093 (2005).

    Article  CAS  Google Scholar 

  7. Guertin, D.A. et al. Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCalpha, but not S6K1. Dev. Cell 11, 859–871 (2006).

    Article  CAS  Google Scholar 

  8. Delgoffe, G.M. & Powell, J.D. mTOR: taking cues from the immune microenvironment. Immunology 127, 459–465 (2009).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  10. Araki, K. et al. mTOR regulates memory CD8 T-cell differentiation. Nature 460, 108–112 (2009).

    Article  CAS  Google Scholar 

  11. Rao, R.R., Li, Q., Odunsi, K. & Shrikant, P.A. The mTOR kinase determines effector versus memory CD8+ T cell fate by regulating the expression of transcription factors T-bet and Eomesodermin. Immunity 32, 67–78 (2010).

    Article  Google Scholar 

  12. Sinclair, L.V. et al. Phosphatidylinositol-3-OH kinase and nutrient-sensing mTOR pathways control T lymphocyte trafficking. Nat. Immunol. 9, 513–521 (2008).

    Article  CAS  Google Scholar 

  13. Yamagata, K. et al. Rheb, a growth factor- and synaptic activity-regulated gene, encodes a novel Ras-related protein. J. Biol. Chem. 269, 16333–16339 (1994).

    CAS  PubMed  Google Scholar 

  14. Yee, W.M. & Worley, P.F. Rheb interacts with Raf-1 kinase and may function to integrate growth factor- and protein kinase A-dependent signals. Mol. Cell. Biol. 17, 921–933 (1997).

    Article  CAS  Google Scholar 

  15. Manning, B.D. & Cantley, L.C. Rheb fills a GAP between TSC and TOR. Trends Biochem. Sci. 28, 573–576 (2003).

    Article  CAS  Google Scholar 

  16. Saucedo, L.J. et al. Rheb promotes cell growth as a component of the insulin/TOR signalling network. Nat. Cell Biol. 5, 566–571 (2003).

    Article  CAS  Google Scholar 

  17. Barnden, M.J., Allison, J., Heath, W.R. & Carbone, F.R. Defective TCR expression in transgenic mice constructed using cDNA-based α- and β-chain genes under the control of heterologous regulatory elements. Immunol. Cell Biol. 76, 34–40 (1998).

    Article  CAS  Google Scholar 

  18. Park, H. et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat. Immunol. 6, 1133–1141 (2005).

    Article  CAS  Google Scholar 

  19. Wensky, A.K. et al. IFN-γ determines distinct clinical outcomes in autoimmune encephalomyelitis. J. Immunol. 174, 1416–1423 (2005).

    Article  CAS  Google Scholar 

  20. Kumar, A. et al. Muscle-specific deletion of rictor impairs insulin-stimulated glucose transport and enhances basal glycogen synthase activity. Mol. Cell. Biol. 28, 61–70 (2008).

    Article  CAS  Google Scholar 

  21. Paul, W.E. What determines Th2 differentiation, in vitro and in vivo? Immunol. Cell Biol. 88, 236–239 (2010).

    Article  CAS  Google Scholar 

  22. Yamane, H., Zhu, J. & Paul, W.E. Independent roles for IL-2 and GATA-3 in stimulating naive CD4+ T cells to generate a Th2-inducing cytokine environment. J. Exp. Med. 202, 793–804 (2005).

    Article  CAS  Google Scholar 

  23. Sarbassov, D.D. et al. Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol. Cell 22, 159–168 (2006).

    Article  CAS  Google Scholar 

  24. Wang, B. et al. Nogo-66 promotes the differentiation of neural progenitors into astroglial lineage cells through mTOR-STAT3 pathway. PLoS ONE 3, e1856 (2008).

    Article  Google Scholar 

  25. Zhou, J. et al. Activation of the PTEN/mTOR/STAT3 pathway in breast cancer stem-like cells is required for viability and maintenance. Proc. Natl. Acad. Sci. USA 104, 16158–16163 (2007).

    Article  CAS  Google Scholar 

  26. Yamamoto, K., Yamaguchi, M., Miyasaka, N. & Miura, O. SOCS-3 inhibits IL-12-induced STAT4 activation by binding through its SH2 domain to the STAT4 docking site in the IL-12 receptor β2 subunit. Biochem. Biophys. Res. Commun. 310, 1188–1193 (2003).

    Article  CAS  Google Scholar 

  27. Yu, C.R. et al. Suppressor of cytokine signaling 3 regulates proliferation and activation of T-helper cells. J. Biol. Chem. 278, 29752–29759 (2003).

    Article  CAS  Google Scholar 

  28. Palmer, D.C. & Restifo, N.P. Suppressors of cytokine signaling (SOCS) in T cell differentiation, maturation, and function. Trends Immunol. 30, 592–602 (2009).

    Article  CAS  Google Scholar 

  29. Ozaki, A., Seki, Y., Fukushima, A. & Kubo, M. The control of allergic conjunctivitis by suppressor of cytokine signaling (SOCS)3 and SOCS5 in a murine model. J. Immunol. 175, 5489–5497 (2005).

    Article  CAS  Google Scholar 

  30. Seki, Y. et al. Expression of the suppressor of cytokine signaling-5 (SOCS5) negatively regulates IL-4-dependent STAT6 activation and Th2 differentiation. Proc. Natl. Acad. Sci. USA 99, 13003–13008 (2002).

    Article  CAS  Google Scholar 

  31. Battaglia, M., Stabilini, A. & Roncarolo, M.G. Rapamycin selectively expands CD4+CD25+FoxP3+ regulatory T cells. Blood 105, 4743–4748 (2005).

    Article  CAS  Google Scholar 

  32. Sauer, S. et al. T cell receptor signaling controls Foxp3 expression via PI3K, Akt, and mTOR. Proc. Natl. Acad. Sci. USA 105, 7797–7802 (2008).

    Article  CAS  Google Scholar 

  33. Haxhinasto, S., Mathis, D. & Benoist, C. The AKT-mTOR axis regulates de novo differentiation of CD4+Foxp3+ cells. J. Exp. Med. 205, 565–574 (2008).

    Article  CAS  Google Scholar 

  34. Ballou, L.M., Selinger, E.S., Choi, J.Y., Drueckhammer, D.G. & Lin, R.Z. Inhibition of mammalian target of rapamycin signaling by 2-(morpholin-1-yl)pyrimido[2,1-α]isoquinolin-4-one. J. Biol. Chem. 282, 24463–24470 (2007).

    Article  CAS  Google Scholar 

  35. Colombetti, S., Basso, V., Mueller, D.L. & Mondino, A. Prolonged TCR/CD28 engagement drives IL-2-independent T cell clonal expansion through signaling mediated by the mammalian target of rapamycin. J. Immunol. 176, 2730–2738 (2006).

    Article  CAS  Google Scholar 

  36. Rathmell, J.C., Farkash, E.A., Gao, W. & Thompson, C.B. IL-7 enhances the survival and maintains the size of naive T cells. J. Immunol. 167, 6869–6876 (2001).

    Article  CAS  Google Scholar 

  37. Stephenson, L.M., Park, D.S., Mora, A.L., Goenka, S. & Boothby, M. Sequence motifs in IL-4Rα mediating cell-cycle progression of primary lymphocytes. J. Immunol. 175, 5178–5185 (2005).

    Article  CAS  Google Scholar 

  38. Lekmine, F. et al. Interferon-gamma engages the p70 S6 kinase to regulate phosphorylation of the 40S S6 ribosomal protein. Exp. Cell Res. 295, 173–182 (2004).

    Article  CAS  Google Scholar 

  39. Lee, K. et al. Mammalian target of rapamycin protein complex 2 regulates differentiation of Th1 and Th2 cell subsets via distinct signaling pathways. Immunity 32, 743–753 (2010).

    Article  CAS  Google Scholar 

  40. Kang, J., Huddleston, S.J., Fraser, J.M. & Khoruts, A. De novo induction of antigen-specific CD4+CD25+Foxp3+ regulatory T cells in vivo following systemic antigen administration accompanied by blockade of mTOR. J. Leukoc. Biol. 83, 1230–1239 (2008).

    Article  CAS  Google Scholar 

  41. Kopf, H., de la Rosa, G.M., Howard, O.M. & Chen, X. Rapamycin inhibits differentiation of Th17 cells and promotes generation of FoxP3+ T regulatory cells. Int. Immunopharmacol. 7, 1819–1824 (2007).

    Article  CAS  Google Scholar 

  42. Valmori, D. et al. Rapamycin-mediated enrichment of T cells with regulatory activity in stimulated CD4+ T cell cultures is not due to the selective expansion of naturally occurring regulatory T cells but to the induction of regulatory functions in conventional CD4+ T cells. J. Immunol. 177, 944–949 (2006).

    Article  CAS  Google Scholar 

  43. Francisco, L.M. et al. PD-L1 regulates the development, maintenance, and function of induced regulatory T cells. J. Exp. Med. 206, 3015–3029 (2009).

    Article  CAS  Google Scholar 

  44. Cobbold, S.P. et al. Infectious tolerance via the consumption of essential amino acids and mTOR signaling. Proc. Natl. Acad. Sci. USA 106, 12055–12060 (2009).

    Article  CAS  Google Scholar 

  45. Kim, S. et al. The apical complex couples cell fate and cell survival to cerebral cortical development. Neuron 66, 69–84 (2010).

    Article  CAS  Google Scholar 

  46. Shu, L. & Houghton, P.J. The mTORC2 complex regulates terminal differentiation of C2C12 myoblasts. Mol. Cell. Biol. 29, 4691–4700 (2009).

    Article  CAS  Google Scholar 

  47. Johnson, M.D., O'Connell, M., Vito, F. & Bakos, R.S. Increased STAT-3 and synchronous activation of Raf-1-MEK-1-MAPK, and phosphatidylinositol 3-Kinase-Akt-mTOR pathways in atypical and anaplastic meningiomas. J. Neurooncol. 92, 129–136 (2009).

    Article  CAS  Google Scholar 

  48. Garcia-Martinez, J.M. & Alessi, D.R. mTOR complex 2 (mTORC2) controls hydrophobic motif phosphorylation and activation of serum- and glucocorticoid-induced protein kinase 1 (SGK1). Biochem. J. 416, 375–385 (2008).

    Article  CAS  Google Scholar 

  49. Dekker, R.J. et al. KLF2 provokes a gene expression pattern that establishes functional quiescent differentiation of the endothelium. Blood 107, 4354–4363 (2006).

    Article  CAS  Google Scholar 

  50. Delgoffe, G.M., Kole, T.P., Cotter, R.J. & Powell, J.D. Enhanced interaction between Hsp90 and raptor regulates mTOR signaling upon T cell activation. Mol. Immunol. 46, 2694–2698 (2009).

    Article  CAS  Google Scholar 

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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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Authors and Affiliations

  1. Department of Oncology, Sidney-Kimmel Comprehensive Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Greg M Delgoffe, Kristen N Pollizzi, Adam T Waickman, Emily Heikamp & Jonathan D Powell

  2. Department of Pharmacology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    David J Meyers

  3. Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Maureen R Horton

  4. Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Bo Xiao & Paul F Worley

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  1. Greg M Delgoffe
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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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Supplementary Figures 1–13 (PDF 9152 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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