Dendritic cell alpha-ketoglutarate regulates Tfh polarization in allergic asthma 2444

Abstract Description 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, like conventional dendritic cells (cDCs), following allergen exposure. Previous data from our lab shows that allergen stimulation induces a distinct metabolic program in cDCs characterized by increased glutaminolysis which results in intracellular accumulation of α-ketoglutarate. In this study, we show that glutamine-derived α-ketoglutarate in cDCs regulates Tfh13 polarization by HIF-1α mediated changes. HIF-prolyl hydroxylase (HIF-PH) blockade caused reduced Tfh13 and germinal center IgE. Deletion of HIF1α in cDCs, in contrast, enhanced Tfh13 polarization and IgE synthesis. Next, we show that HIF-PH inhibitor treatment in allergen-sensitized mice induces tolerance characterized by reduced asthmatic airway resistance, antigen-specific IgE production, and mast cell degranulation. Finally, we reveal distinct costimulatory molecule changes on allergen-stimulated cDCs that are reversed with HIF-PH inhibitor treatment on both mouse and human cDC2s. Thus, we demonstrate that α-ketoglutarate production regulates gene expression changes critical for allergen-induced cDC activation that leads to induction of Tfh13 cells and further antigen-specific IgE formation. Therefore, this data reveals promising new pharmacological targets for IgE-mediated allergic disease. Funding Sources NHLBI-NIH R01HL162991; NIAID-NIH R56AI139658 Topic Categories Immediate Hypersensitivity, Asthma, and Allergic Responses (HYP)