In healthy individuals, T cells generally exist in a state of equilibrium or homeostasis. This homeostasis is achieved by a tight and dynamic regulation of signaling cascades that control T cell numbers, localization, metabolism, and differentiation at any given time. Dysregulation of T cell homeostasis underlies several immunopathologic conditions including autoimmune diseases and cancer, hence the need to better understand molecular mechanisms that control T cell homeostasis. The mechanistic target of rapamycin (mTOR) is a critical hub within several important signaling cascades that are operational throughout the life of a T cell from thymic development to antigen encounter and beyond. While significant progress has been made in uncovering the roles of mTOR in various aspects of T cell immunity, the molecular mechanisms that dynamically regulate the threshold of mTOR signaling at various stages of the T cell life cycle and how this contributes to T cell homeostasis are poorly understood. mTOR functions as the enzymatic nucleus of two multiprotein complexes designated mTOR complex 1 (mTORC1) and mTORC2. We investigated the role of mTORC2 in naïve T cell homeostasis and the dynamic biochemical regulation of mTORC2 signaling by Sin1 and its isoforms. This led us to uncover a previously unappreciated but fundamental aspect of T cell biology; active mTORC2 signaling in naïve T cells suppresses bone marrow homing and in this manner allows T cells recirculate more efficiently through secondary lymphoid organs for better immune-surveillance. Furthermore, our exploration of the dynamic biochemical regulation of mTORC2 in naïve versus activated T cells revealed a potential mechanism through which dynamic mTORC2 signaling is achieved. We found that the overall strength of mTOR signaling is controlled at the level of transcriptional expression of mTOR and its adaptors by TCR stimulation. More broadly, we also investigated the biochemical regulation of mTORC2 by Sin1 isoforms, taking advantage of their domains to understand how various upstream signals might control mTORC2 activity. Through these investigations, we established that Sin1 isoforms differentially regulate mTORC2 response to Pi3K and non-Pi3K signals as well as mTORC2 target substrate specificity.
|School Location:||United States -- Connecticut|
|Source:||DAI-B 79/05(E), Dissertation Abstracts International|
|Subjects:||Biology, Biochemistry, Immunology|
|Keywords:||Bone Marrow Homing, Dynamic Regulation of mTOR, Native T Cell Homeostasis, Sin1, mTOR, mTORC2|
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