Date of Award

1-1-2016

Embargo Period

1-1-2019

Document Type

Thesis - MUSC Only

Degree Name

Master of Biomedical Science

Department

Microbiology and Immunology

College

College of Graduate Studies

First Advisor

Shikhar Mehrotra

Second Advisor

Craig Beeson

Third Advisor

Chenthamarakshan Vasu

Fourth Advisor

Chrystal Paulos

Fifth Advisor

Kenneth Chavin

Sixth Advisor

Natalie Sutkowski

Abstract

Our understanding of T cell metabolism and its effect on their immune response is still limited. In fact, T cell subsets show distinct metabolic phenotype that is changeable between oxidative phosphorylation and glycolysis. This dynamic metabolism is associated with up regulation and down regulation of different metabolic pathways. We report here that uncoupling protein 2 (UCP2) whose expression is up regulated after T cell activation is important for the expression of pyruvate dehydrogenase kinase (PDK). PDK is an inhibitor of pyruvate dehydrogenase, a key bifurcation point between T cell glycolytic and oxidative metabolism. To investigate the effect of UCP2 on in vitro activated T cells we used either a global knock-out mouse model for UCP2 or used Genipin – a potent pharmacological inhibitor of UCP2. Our data shows that while UCP2-KO T cells exhibit increased CD44hi CD62Llo effector population after activation, there was a decrease in IFNγ production and a decrease in the expression of transcription factor associated with T cell effector phenotype, T-bet. However, an increased expression of IL-10 was observed in T cells that had reduced UCP-2 expression (either genetically or pharmacologically). Using real time PCR and flow cytometry, we also observed that UCP-2 inhibition promoted type 1 regulatory T cells (Tr1) phenotype by increasing the expression of aryl hydrocarbon receptor (AHR) and CD73. This was supported by increase in the suppressive activity of in vitro polarized UCP2-KO T regulatory cells. Our data indicates that UCP2 expression limits the plasticity of effector T cells towards regulatory T cells, and could be used to either improve effector T cell response against tumor, or promote regulatory T cell mediated tolerance in autoimmune diseases.

Rights

All rights reserved. Copyright is held by the author.

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