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


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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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

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.

Correspondence to Hongbo Chi.

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The authors declare no competing financial interests.

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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).

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