DOI
https://doi.org/10.25772/0BJE-3450
Defense Date
2023
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Microbiology & Immunology
First Advisor
Rebecca K. Martin
Abstract
Allergic asthma is among the most common respiratory diseases globally, affecting roughly 300 million people worldwide and causing significant morbidity and mortality. Initiation of allergic responses in asthma requires activation of a specialized subset of T follicular helper (Tfh) cells called Tfh13 cells. Tfh13 cell differentiation from naïve CD4+ T cells is induced by antigen presenting cells, such as conventional dendritic cells (cDCs), following allergen exposure. Allergen stimulation induces a distinct metabolic program in cDCs characterized by increased glutaminolysis which results in intracellular accumulation of α-ketoglutarate. Inhibition of glutaminolysis suppresses Tfh13 cell differentiation and promotes inhibitory T follicular regulatory (Tfr) cell activation in vivo. Further, glutamine-derived α-ketoglutarate was shown to promote epigenetic modifications via the Jumonji-domain containing (JmjC) family of histone demethylases, which are critical for DC activation and subsequent Tfh13 cell induction and IgE production. Indeed, JmjD3 blockade caused reduced Tfh13 and germinal center IgE. Finally, we show that glutaminase inhibitor treatment in allergen-sensitized mice induces allergen tolerance characterized by reduced asthmatic airway resistance, antigen-specific IgE production, and airway mast cell degranulation. Additionally, D-2-hydroxyglutarate, a metabolic by-product of α-ketoglutarate which acts as a competitive inhibitor of al JmjC enzymes, also suppresses Tfh13 and Th2 polarization while promoting Tfr induction. Thus, we demonstrate that α-ketoglutarate production via glutaminase is a critical enhancer of allergen-induced cDC activation and is crucial for induction of Tfh13 cells and antigen-specific IgE formation. Therefore, glutaminase and JmjD3 inhibitors promise to provide a new pharmacological strategy for controlling IgE-mediated allergic disease.
Rights
© Anuj Tharakan
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
5-1-2023