Dendritic Cell α-Ketoglutarate Regulates Tfh Polarization in Allergy

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 show that glutaminase or HIF-PH inhibitor treatment in allergen-sensitized mice induces allergen tolerance characterized by reduced asthmatic airway resistance, antigen-specific IgE production, and airway mast cell degranulation. Thus, we demonstrate that α-ketoglutarate production regulates epigenetic and gene expression changes critical for allergic sensitization by cDC2s following allergen exposure, leading to induction of Tfh13 cells and antigen-specific IgE formation. Therefore, this glutaminase 1-JmjD3/HIF-PH axis represents a promising new target for controlling IgE-mediated allergic disease pharmacologically.