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mTORC2 in Dendritic Cells Restrains mTORC1-regulated Metabolic Activity and Their T Cell Stimulatory Function in Transplantation

Watson, Alicia (2018) mTORC2 in Dendritic Cells Restrains mTORC1-regulated Metabolic Activity and Their T Cell Stimulatory Function in Transplantation. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Mechanistic target of rapamycin (mTOR) complexes (C) 1 and 2 play important roles in determining the differentiation and function of immune cells. While suppression of mTORC1 antagonizes dendritic cell (DC) maturation and suppresses graft rejection, the role of mTORC2 in DC in determining host responses to transplanted tissue is undefined. Utilizing an innovative mouse model in which mTORC2 was deleted specifically in CD11c+ DC (TORC2DC-/-), we show that transplantation of minor histocompatibility (m-Ag) antigen (HY)-mismatched skin grafts from TORC2DC-/- donors into wild-type recipients results in accelerated rejection, characterized by enhanced CD8+ T cell responses in the graft and regional lymphoid tissue. Augmented CD8+ T cell responses were also observed in skin grafts from TORC2DC-/- B6 donors into major histocompatibility (MHC) mismatched BALB/c recipients, and in a delayed-type hypersensitivity model in which mTORC2 was absent in cutaneous DC. These responses could be ascribed to an increased T cell stimulatory phenotype of TORC2DC-/- and not to enhanced lymph node homing of the cells. These findings suggest mTORC2 in skin DC plays an important role in initiation of rejection and restrains effector CD8+ T cell responses. In addition, we describe a novel metabolic regulatory role of mTORC2 in DC, whereby mTORC2 restrains glycolytic bias and mitochondrial dysfunction by regulating mTORC1-driven metabolic function. These studies have implications for understanding the impact of conventional and new generation mTOR inhibitors that target mTORC2 in the multiple clinical contexts, including transplantation and cancer therapeutics.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Watson, AliciaAwats2886@gmail.comalw128
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorThomson, Angusthomsonaw@upmc.edu
Committee ChairDeFrances, Mariedefrancesmc@upmc.edu
Committee MemberTurnquist, Hethhet5@pitt.edu
Committee MemberSoto-Gutierrez, Alejandroals208@pitt.edu
Committee MemberDelgoffe, Gregdelgoffeg@upmc.edu
Date: 27 November 2018
Date Type: Publication
Defense Date: 17 October 2018
Approval Date: 27 November 2018
Submission Date: 24 November 2018
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 145
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Cellular and Molecular Pathology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: N/A
Date Deposited: 27 Nov 2018 18:02
Last Modified: 27 Nov 2018 18:02
URI: http://d-scholarship.pitt.edu/id/eprint/35552

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