Metabolic perturbations in conventional dendritic cells modulate Tfh13 induction in asthmatic sensitization

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Abstract Allergic asthma is among the most common chronic lung diseases worldwide, and despite advances in treatment asthma prevalence continues to rise globally. Allergic asthma is largely driven by IgE antibodies that target environmental allergens. The production of allergen-specific IgE requires T follicular helper 13 cells (Tfh13) which must first be polarized by dendritic cells (DCs). However, a critical knowledge gap remains: how do DCs gain the ability to induce Tfh13s? By studying DC responses to allergic stimuli, we have determined that allergens induce a unique metabolic program in DCs, characterized by increased glutamine metabolism. We identified that allergen stimulated DCs exhibit aberrant TCA cycle metabolism, which leads to accumulation of α-ketoglutarate and succinate and reduced levels of fumarate and malate. We hypothesize that DC glutamine metabolism after allergen exposure is critical for polarization of Tfh13s. The goals of this proposal are (1) to ascertain effector mechanisms downstream of glutamine metabolism that induce Tfh13 polarization, (2) to elucidate key mechanistic changes in DCs induced by aberrant TCA cycle metabolites, and (3) to determine the translatability of this pathway into human DCs. This work promises an exciting new avenue for development of novel therapeutic targets and preventive strategies for the management of allergic asthma.