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The tumor suppressor Tsc1 enforces quiescence of naive T cells to promote immune homeostasis and function

Nature Immunology volume 12, pages 888–897 (2011)Cite this article

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Abstract

The mechanisms that regulate T cell quiescence are poorly understood. We report that the tumor suppressor Tsc1 established a quiescence program in naive T cells by controlling cell size, cell cycle entry and responses to stimulation of the T cell antigen receptor. Abrogation of quiescence predisposed Tsc1-deficient T cells to apoptosis that resulted in loss of conventional T cells and invariant natural killer T cells. Loss of Tsc1 function dampened in vivo immune responses to bacterial infection. Tsc1-deficient T cells had more activity of the serine-threonine kinase complex mTORC1 but less mTORC2 activity, and activation of mTORC1 was essential for the disruption of immune homeostasis. Therefore, Tsc1-dependent control of mTOR is crucial in actively maintaining the quiescence of naive T cells to facilitate adaptive immune function.

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Figure 1: Tsc1 deficiency leads to disrupted homeostasis of peripheral T cell populations.
Figure 2: Deletion of Tsc1 results in excessive apoptosis of T cells.
Figure 3: Tsc1-deficient T cells die via the Bcl-2 family–dependent intrinsic apoptotic pathway.
Figure 4: Tsc1 deficiency causes cell-autonomous loss of quiescence in vivo and hyperactive responses to TCR stimulation.
Figure 5: Tsc1-dependent gene expression programs.
Figure 6: Loss of T cell quiescence results from inducible deletion of Tsc1 and is independent of cell survival.
Figure 7: Tsc1 regulates the activity of mTORC1 and mTORC2, and mTORC1 activation is essential for the disruption of immune quiescence and homeostasis.
Figure 8: Tsc1 deficiency dampens antibacterial immune response in vivo.

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Acknowledgements

We thank P. Ohashi (University of Toronto) for Akt1-transgenic mice; T. Ludwig (Columbia University) for Rosa26-Cre-ERT2 mice; R. Cross, G. Lennon and S. Morgan for cell sorting; and the National Institutes of Health Tetramer Facility for the CD1d-PBS57 tetramer. Supported by the US National Institutes of Health (K01 AR053573 and R01 NS064599), the Arthritis Foundation, the Lupus Research Institute and the American Lebanese Syrian Associated Charities (H.C.).

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Authors and Affiliations

  1. Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA

    Kai Yang, Douglas R Green, Weifeng He & Hongbo Chi

  2. Hartwell Center for Bioinformatics and Biotechnology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA

    Geoffrey Neale

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Contributions

K.Y. designed and did cellular, molecular and biochemical experiments and contributed to the writing of the manuscript; G.N. did bioinformatic analyses; D.R.G. contributed genetic models and conceptual insights; W.H. contributed to cell purification; and H.C. designed experiments, wrote the manuscript and provided overall direction.

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Correspondence to Hongbo Chi.

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Yang, K., Neale, G., Green, D. et al. The tumor suppressor Tsc1 enforces quiescence of naive T cells to promote immune homeostasis and function. Nat Immunol 12, 888–897 (2011). https://doi.org/10.1038/ni.2068

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