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