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.
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.
|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|
|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|
|Tan, Haiyan; Yang, Kai; Li, Yuxin et al. (2017) Integrative Proteomics and Phosphoproteomics Profiling Reveals Dynamic Signaling Networks and Bioenergetics Pathways Underlying T Cell Activation. Immunity 46:488-503|
|Zeng, Hu; Cohen, Sivan; Guy, Cliff et al. (2016) mTORC1 and mTORC2 Kinase Signaling and Glucose Metabolism Drive Follicular Helper T Cell Differentiation. Immunity 45:540-554|
|Wei, Jun; Long, Lingyun; Yang, Kai et al. (2016) Autophagy enforces functional integrity of regulatory T cells by coupling environmental cues and metabolic homeostasis. Nat Immunol 17:277-85|
|Huang, Gonghua; Wang, Yanyan; Vogel, Peter et al. (2015) Control of IL-17 receptor signaling and tissue inflammation by the p38?-MKP-1 signaling axis in a mouse model of multiple sclerosis. Sci Signal 8:ra24|
|Liu, Chaohong; Chapman, Nicole M; Karmaus, Peer W F et al. (2015) mTOR and metabolic regulation of conventional and regulatory T cells. J Leukoc Biol 97:837-847|
|Shrestha, Sharad; Yang, Kai; Guy, Cliff et al. (2015) Treg cells require the phosphatase PTEN to restrain TH1 and TFH cell responses. Nat Immunol 16:178-87|
|Zeng, Hu; Chi, Hongbo (2015) Metabolic control of regulatory T cell development and function. Trends Immunol 36:3-12|
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