Journal
EUROPEAN JOURNAL OF IMMUNOLOGY
Volume 41, Issue 11, Pages 3361-3370Publisher
WILEY-BLACKWELL
DOI: 10.1002/eji.201141411
Keywords
Cell survival; Mammalian target of rapamycin; Signal transduction; T cells; Tuberous sclerosis complex
Categories
Funding
- National Institutes of Health [R01AI076357, R01AI079088, R21AI079873]
- American Cancer Society
- American Heart Association
- Food Allergy and Anaphylaxis Network
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The mammalian target of rapamycin (mTOR) is a key regulator of cell growth and metabolism. It associates with multiple proteins and forms two distinct signaling complexes, mTORC1 and mTORC2. Accumulating evidence has revealed critical roles for intact mTOR signaling during T-cell activation and responses to microbial infection. However, the importance of mTOR regulation in T cells has yet to be explored. The TSC1/TSC2 complex has been shown to inhibitmTORC1 signaling in cell line models. We show here that deletion of TSC1 in the murine T-cell lineage results in a dramatic reduction of the peripheral T-cell pool, correlating with increased cell death. While mTORC1 is constitutively activated, mTORC2 signaling, reflected by Akt phosphorylation and activity, is decreased in TSC1-deficient T cells. Furthermore, TSC1-deficient T cells contain elevated reactive oxygen species (ROS) and exhibit decreased mitochondrial content and membrane potential, which is correlated with the activation of the intrinsic death pathway. Overall, our results demonstrate that TSC1 differentially regulates mTORC1 and mTORC2 activity, promotes T-cell survival, and is critical for normal mitochondrial homeostasis in T cells.
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