Aberrant activation of mTOR, a central regulator of cell growth and metabolism, is a common molecular event in a number of human malignancies including T-lymphoblastic leukemia (T-ALL), a hematological cancer with poor prognosis. Emerging evidence also highlights a crucial role of mTOR signaling in T cell activation and differentiation. The requirement of mTOR for T cell responses is reflective of the unique feature of T cell activation, in that actively cycling T cells undergo massive clonal expansion with a rate of proliferation (doubling every 5-6 hours) exceeding that of any other cells in the adult mammalian system. Concomitant with T cell activation is the reprogramming of the metabolic machinery. Conversely, in the absence of antigen stimulation, T cells exist in a state known as quiescence defined by a small cell size and exit from the cell cycle. Quiescence has been suggested to reduce the energy and space required to maintain a large repertoire of lymphocytes, but how it is regulated remains poorly defined. We recently identified that Tsc1 enforces T cell quiescence by actively controlling mTOR activity. We hypothesize that Tsc1 and mTOR signaling orchestrates a metabolic checkpoint for naive T cell quiescence, and loss of this control mechanism exacerbates leukemia genesis via metabolic dysregulation and inflammatory pathways. We will test this hypothesis by establishing the metabolic and signaling mechanisms in Tsc1-dependent regulation of T cell quiescence, and determining how these Tsc1-mediated effector pathways contribute to the development of leukemia in murine models and human T-ALL. We predict our studies will establish a new paradigm on our understanding of T cell quiescence by linking this process to metabolic pathways for the first time, and by establishing the functional significance of quiescence enforcement on leukemogenesis and tumor-related inflammation. Insights gained from this project will likely lead to the identificatio of innovative strategies (e.g. targeting metabolic and inflammatory pathways, in addition to inhibiting mTOR) for leukemia intervention.
T cells play a central role in the maintenance of immune homeostasis and regulation of immune responses. T cells depend on the metabolic pathways mediated by mTOR signaling to execute these functions, and dysregulation of this process leads to leukemia and immune-mediated diseases. Therefore, a better understanding of the molecules and pathways in T cells is essential for our efforts to prevent and treat these disorders.
|Zeng, Hu; Cohen, Sivan; Guy, Cliff et al. (2016) mTORC1 and mTORC2 Kinase Signaling and Glucose Metabolism Drive Follicular Helper T Cell Differentiation. Immunity 45:540-54|
|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|
|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|
|Huang, Gonghua; Wang, Yanyan; Vogel, Peter et al. (2015) Control of IL-17 receptor signaling and tissue inflammation by the p38Î±-MKP-1 signaling axis in a mouse model of multiple sclerosis. Sci Signal 8:ra24|
|Wei, Jun; Yang, Kai; Chi, Hongbo (2014) Cutting edge: Discrete functions of mTOR signaling in invariant NKT cell development and NKT17 fate decision. J Immunol 193:4297-301|
|Shrestha, Sharad; Yang, Kai; Wei, Jun et al. (2014) Tsc1 promotes the differentiation of memory CD8+ T cells via orchestrating the transcriptional and metabolic programs. Proc Natl Acad Sci U S A 111:14858-63|
|Chapman, Nicole M; Chi, Hongbo (2014) mTOR signaling, Tregs and immune modulation. Immunotherapy 6:1295-311|