Author ORCID Identifier
https://orcid.org/0000-0002-7030-171X
Defense Date
2026
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Clinical and Translational Sciences
First Advisor
Rebecca K Martin
Second Advisor
Jinze Liu
Third Advisor
Patricia Sime
Fourth Advisor
John Ryan
Fifth Advisor
Michael Lacy
Abstract
Initiation of allergic responses requires activation of specialized subsets of T follicular helper (Tfh) cells called Tfh13 cells. Differentiation of these cells from naïve CD4+ T cells is induced by antigen presenting cells, such as type 2 conventional dendritic cells (cDC2s), following allergen exposure. Here we show that allergen stimulation induces a distinct metabolic program in cDC2s 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 in cDC2s regulates Tfh13 polarization by modulation of JmjD3 mediated histone demethylation and modulation of HIF- 1α activity. JmjD3 or HIF- prolyl hydroxylase (HIF- PH) blockade reduced Tfh13 and germinal center IgE production. Genetic deletion of HIF- 1α in cDCs, in contrast, enhanced Tfh13 polarization and IgE synthesis. Finally, we demonstrate that α- ketoglutarate production regulates epigenetic and gene expression changes critical for allergic sensitization by cDC2s following allergen exposure. We characterize a novel transcriptomic and metabolic framework that dictates the balance between allergic sensitization and immune tolerance. Integrating gene expression findings with established metabolic models, this study demonstrates that Alternaria induces a glutaminase 1-JmjD3/HIF-PH axis, leading to α-ketoglutarate accumulation, HIF-1α degradation, and subsequent Tfh13-mediated IgE production.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
9-15-2026