The T Cell-Intrinsic Role of Peroxisome Proliferator-Activated Receptor Delta in T Cell Development and Effector Function
Year: 2018
Type: dissertation
Abstract: The nuclear receptor peroxisome proliferator-activated receptor delta (PPARd) is a sensor of fatty acids and functions as a transcriptional regulator of various processes. PPARd has been shown to have anti-inflammatory activities in the immune system by promoting alternative macrophage activation; however, the role of PPARd in the T cell compartment is not well understood. This thesis aimed to investigate the role of PPARd in T cell development and effector function. To this end, we generated mice where PPARd was deleted specifically in T cells starting at either the CD4-CD8- double negative (DN) 2 stage or double positive stage of thymocyte development, and used them as tools to study the function of PPARd in the T cell compartment. First, this work uncovered a novel role of PPARd in T cell development. We found that either whole body PPARd-deficient mice or mice with PPARd-deletion starting at the DN2 stage had reduced thymic cellularity that was evident from the T cell receptor (TCR)-b selection step and onwards. This loss in thymocyte cell number related to defects in the ability of PPARd-deficient thymocytes to undergo repeated cell division at the DN3 stage. Our work further revealed that PPARd was required for promoting the expression of genes involved in glycolysis, the tricarboxylic acid cycle, the electron transport chain and lipogenesis. This study is amongst the first to demonstrate a direct role of a PPAR family member in T cell development. In the second part of this study, we used mice where PPARd was deleted at a later stage in thymocyte development to study the role of PPARd in mature T cells. These studies revealed that these T cell-specific PPARd-deficient mice had a normal thymus, but developed more severe T helper (Th) 17-mediated inflammation during experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. This more severe disease related in part to PPARd-deficient T cells being more prone to differentiate towards the Th17 lineage. Together, our research highlights the T cell-intrinsic role of PPARd in supporting T cell development and suppressing central nervous system autoimmunity, making this molecule an attractive therapeutic target for treatment of Th17-mediated diseases.
Source: TSpace (University of Toronto)
Author: Fei Zhao
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2897148378