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Immunometabolic requirements of T cell activation and exhaustion

Scharping, Nicole (2019) Immunometabolic requirements of T cell activation and exhaustion. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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The metabolic requirements of T cells depend on activation, differentiation state, and functionality. These metabolic requirements are integral to T cell function in an acute activation setting, but can become a barrier to function in chronic disease. In acute activation, when CD8+ effector T cells become activated, they immediately switch to prioritizing glycolysis via PDHK1. This allows effector T cells to release cytokine mRNA from glycolytic enzyme regulation, allowing immediate protein synthesis and T cell effector function. In the setting of disease, effector T cells that infiltrate a tumor experience the immunologic and metabolically suppressive tumor microenvironment (TME), which in combination with chronic T cell activation inherent to the environment, causes effector T cells to differentiate into dysfunctional, exhausted T cells. The exhausted T cells also lose mitochondrial mass and function, creating a metabolic disadvantage for the T cell that contributes to their dysfunctional state. This loss of mitochondria is due to repression of mitochondrial biogenesis, mediated by PGC1α. T cell functionality can be restored in the TME with enforced PGC1α expression, which leads to decreased tumor burden and increased survival in mouse melanoma. We also have shown exhausted T cells suffer from additional metabolic disadvantages – decreased fatty acid oxidation. This causes the exhausted T cells to store lipids rather than burn them as fuel. This phenomenon is due to chronic T cell activation under hypoxic conditions, causing dysfunctional mitochondrial to produce excessive mitochondrial reactive oxygen species (ROS). By enforcing fatty acid oxidation by overexpressing PPARγ, we can improve T cell functionality in the TME. Finally, targeting the metabolically suppressive TME is another avenue for bolstering T cell function. By using mitochondrial complex I inhibitor metformin in mouse melanoma, we can dramatically decrease tumor hypoxia, reoxygenating the TME, and in combination with immunotherapeutic checkpoint blockade, decrease tumor burden and increase mouse survival. Together, this thesis elucidates many immunometabolic requirements of T cell activation and exhaustion, allowing us to better understand how biology and metabolism intersect in T cell function, and informs upon designing therapies that better target T cell or TME metabolism to improve cancer immunotherapy.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Scharping, Nicolenes63@pitt.edunes630000-0001-9373-4617
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairDelgoffe,
Committee MemberFerris,
Committee MemberKane,
Committee MemberVan Houten,
Committee MemberVignali,
Date: 29 May 2019
Date Type: Publication
Defense Date: 12 April 2019
Approval Date: 29 May 2019
Submission Date: 4 May 2019
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 263
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Immunology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: immunology, metabolism, mitochondria, cancer, T cell exhaustion, immunotherapy
Date Deposited: 29 May 2019 19:08
Last Modified: 29 May 2021 05:15


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