Mature T cells exit the thymus and circulate through the blood and peripheral lymphoid organs in a quiescent state characterized by decreased cell size and metabolic activity and exit from the active cell cycle (G0). Quiescence has been suggested to reduce the energy and space required to maintain a large repertoire of lymphocytes, but identities of the regulatory factors are poorly defined. Consequently, little is known whether and how the maintenance of T cell quiescence contributes to immune responses in vivo. We found that deletion of Tsc1, a tumor suppressor gene in mTOR signaling, leads to the loss of T cell quiescence (characterized by increased cell growth and cycling) that predisposes these cells to apoptotic death. Tsc1 functions as part of the Tsc1/Tsc2 complex to restrain activity of mTORC1, a central regulator of cell growth and metabolism. Our published work therefore establishes Tsc1 as a bona fide factor for T cell quiescence. To explore the mechanistic basis and functional effects of T cell quiescence, we found in our preliminary studies that Tsc1 deficiency upregulated the metabolic machinery and induced aberrant expression of Myc, a master transcription factor for T cell metabolic reprogramming. From the functional aspects, loss of Tsc1 in T cells upregulated mTORC1 activity and impaired antigen-specific responses against bacterial infections. Conversely, depletion of mTORC1 activity prevented the exit of T cells from quiescence upon TCR stimulation, but this also had a detrimental effect on adaptive immune responses. These results indicate that productive adaptive immunity requires proper control of mTORC1 and metabolic activities that in turn dictate quiescence establishment and exit. Our central hypothesis is: T cell quiescence requires the interplay between Tsc1/mTORC1 signaling and Myc-dependent metabolic programs, and dysregulated establishment or exit of T cell quiescence disrupts adaptive immunity. Specifically, we ask: how is T cell quiescence established? Does enforcement of T cell quiescence play a crucial role in immune responses? How do T cells exit quiescence upon antigen stimulation? Whereas there has been remarkable progress in our understanding of how mTOR signaling and metabolic pathways regulate T cell activation and differentiation, their involvement in T cell quiescence remains essentially unexplored. Insights gained from this application may significantly impact our understanding of T cell quiescence and manifest legitimate therapeutic opportunities.

Public Health Relevance

T cell quiescence plays a central role in the maintenance of immune homeostasis and regulation of immune responses towards infections. Therefore, a better understanding of the molecules and pathways involved in T cell quiescence is essential for future efforts to prevent and treat infectious and other immune-mediated diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI101407-03
Application #
8862357
Study Section
Cellular and Molecular Immunology - B Study Section (CMIB)
Program Officer
Mallia, Conrad M
Project Start
2013-06-01
Project End
2016-05-31
Budget Start
2015-06-01
Budget End
2016-05-31
Support Year
3
Fiscal Year
2015
Total Cost
Indirect Cost
Name
St. Jude Children's Research Hospital
Department
Type
DUNS #
067717892
City
Memphis
State
TN
Country
United States
Zip Code
38105
Shi, Hao; Liu, Chaohong; Tan, Haiyan et al. (2018) Hippo Kinases Mst1 and Mst2 Sense and Amplify IL-2R-STAT5 Signaling in Regulatory T Cells to Establish Stable Regulatory Activity. Immunity 49:899-914.e6
Du, Xingrong; Wen, Jing; Wang, Yanyan et al. (2018) Hippo/Mst signalling couples metabolic state and immune function of CD8?+ dendritic cells. Nature 558:141-145
Zeng, Hu; Yu, Mei; Tan, Haiyan et al. (2018) Discrete roles and bifurcation of PTEN signaling and mTORC1-mediated anabolic metabolism underlie IL-7-driven B lymphopoiesis. Sci Adv 4:eaar5701
Newton, Ryan H; Shrestha, Sharad; Sullivan, Jenna M et al. (2018) Maintenance of CD4 T cell fitness through regulation of Foxo1. Nat Immunol 19:838-848
Chapman, Nicole M; Zeng, Hu; Nguyen, Thanh-Long M et al. (2018) mTOR coordinates transcriptional programs and mitochondrial metabolism of activated Treg subsets to protect tissue homeostasis. Nat Commun 9:2095
Yang, Kai; Blanco, Daniel Bastardo; Chen, Xiang et al. (2018) Metabolic signaling directs the reciprocal lineage decisions of ?? and ?? T cells. Sci Immunol 3:
Yang, Kai; Blanco, Daniel Bastardo; Neale, Geoffrey et al. (2017) Homeostatic control of metabolic and functional fitness of Treg cells by LKB1 signalling. Nature 548:602-606
Zeng, Hu; Chi, Hongbo (2017) mTOR signaling in the differentiation and function of regulatory and effector T cells. Curr Opin Immunol 46:103-111
Karmaus, Peer W F; Herrada, Andrés A; Guy, Cliff et al. (2017) Critical roles of mTORC1 signaling and metabolic reprogramming for M-CSF-mediated myelopoiesis. J Exp Med 214:2629-2647
Shi, Lewis Zhichang; Saravia, Jordy; Zeng, Hu et al. (2017) Gfi1-Foxo1 axis controls the fidelity of effector gene expression and developmental maturation of thymocytes. Proc Natl Acad Sci U S A 114:E67-E74

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