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 #
5R01AI101407-02
Application #
8663689
Study Section
Cellular and Molecular Immunology - B Study Section (CMIB)
Program Officer
Mallia, Conrad M
Project Start
2013-06-01
Project End
2018-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
2
Fiscal Year
2014
Total Cost
$437,500
Indirect Cost
$187,500
Name
St. Jude Children's Research Hospital
Department
Type
DUNS #
067717892
City
Memphis
State
TN
Country
United States
Zip Code
38105
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