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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 888897 (2011) | Download Citation

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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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.).

Author information

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.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Hongbo Chi.

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DOI

https://doi.org/10.1038/ni.2068