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The kinases aurora B and mTOR regulate the G1–S cell cycle progression of T lymphocytes

Nature Immunology volume 8, pages 64–73 (2007)Cite this article

Abstract

CD28-deficient T cells arrest at the G1–S transition of the cell cycle. Here we show that this is controlled by the kinase aurora B, which exists in a complex with survivin and mammalian target of rapamycin (mTOR). Expression of aurora B in Cd28−/− T cells augmented phosphorylation of mTOR substrates, expression of cyclin A, hyperphosphorylation of retinoblastoma protein and activation of cyclin-dependent kinases 1 and 2 and promoted cell cycle progression. Interleukin 2 enhanced aurora B activity, and inactive aurora B prevented interleukin 2–induced proliferation. Moreover, expression of aurora B restored Cd28−/− T cell proliferation and promoted inflammation in vivo. These data identify aurora B, along with survivin and mTOR, as a regulator of the G1–S checkpoint in T cells.

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Figure 1: Defective aurora B expression in primed hyporesponsive Cd28−/− T cells.
Figure 2: Aurora B interacts with survivin.
Figure 3: Aurora B is expressed in the G1 and S phases and regulates G1- and S-phase proteins.
Figure 4: Aurora B and survivin promote G1-S cell cycle progression but not cytokine production in Cd28−/− T cells.
Figure 5: Aurora B kinase activity and cell cycle control depend on mTOR.
Figure 6: Aurora B associates with and regulates the activity of mTOR, p70S6k and 4E-BP1.
Figure 7: IL-2 regulates aurora B, and aurora B is required for IL-2R-induced cell cycle progression.
Figure 8: Aurora B is sufficient to induce proliferation of Cd28−/− T cells in vivo.
Figure 9: Aurora B restores the ability of Cd28−/− TH2 cells to promote lung inflammation.

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Acknowledgements

We thank M. Tatsuka (Research Institute for Radiation Biology and Medicine, Hiroshima University) for aurora B cDNA, and A. Song, W. Duan, X. Tang and Y. Adams for technical assistance. The cDNA to construct Mig vectors expressing survivin and dominant negative survivin was provided by D. Altieri (University of Massachusetts Medical School). Supported by the US National Institutes of Health (AI50498 and AI49453 to M.C.) and the Universitywide AIDS Research Program (J.S.). This is manuscript 764 from the La Jolla Institute for Allergy and Immunology.

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Authors and Affiliations

  1. Division of Molecular Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, 92037, California, USA

    Jianxun Song, Shahram Salek-Ardakani, Takanori So & Michael Croft

  2. Institute of Immunology PLA, The Third Military Medical University, Chongqing, China

    Jianxun Song

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Contributions

J.S., S.S.-A., T.S. and M.C. designed the research and analyzed the data; J.S., S.S.-A. and T.S. did the research; and M.C. wrote the manuscript.

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Correspondence to Michael Croft.

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Supplementary information

Supplementary Fig. 1

Aurora B is expressed and active in T cells. (PDF 55 kb)

Supplementary Fig. 2

Aurora B expression and activity in naive T cells. (PDF 71 kb)

Supplementary Fig. 3

MEK/Erk regulate aurora B activity and G1-S transition. (PDF 264 kb)

Supplementary Fig. 4

Aurora B activity induced by IL-2R is dependent on mTor. (PDF 70 kb)

Supplementary Methods (PDF 100 kb)

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Song, J., Salek-Ardakani, S., So, T. et al. The kinases aurora B and mTOR regulate the G1–S cell cycle progression of T lymphocytes. Nat Immunol 8, 64–73 (2007). https://doi.org/10.1038/ni1413

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