The role of Glutamine metabolism in conventional Dendritic Cells and the downstream polarization of CD4+ T-cells 2258081

Abstract Introduction Allergy induced asthma is defined as a chronic disease that plagues the airways of approximately 60% all asthmatic patients. Allergic asthma is characterized through the symptomatology of inflamed or thickened airways, over production of mucus, and airway hyperresponsiveness (AHR). This disease is typically initiated by irritants such as pet dander, pollen, fungi, and pollutants eliciting a type 2 immune response. Within the type 2 classified immune response there are several immune cells involved. Allergen specific IgE promotes mast cell activation and degranulation in both humans and animals. Initiation of this response depends on activation of a specialized subset of T follicular helper (Tfh) cells called Tfh13 which induces high-affinity IgE production by B cells. Tfh13 cell differentiation from naïve CD4+ T cells is induced by antigen presenting cells, such as conventional dendritic cells (cDCs), following allergen exposure. Recent studies have identified cellular metabolism as a key regulators of DC phenotype and function. Methods C57BL/6 mice were intranasally stimulated with Alternaria Alternata prior to treatment with CB839, a glutaminase I inhibitor. We then intraperitoneally (i.p.) administered cell permeable succinate or alpha-ketoglutarate. On day 8 we euthanized mice and collected mediastinal draining lymph nodes. Results Previous lab members found that stimulation with the allergen Alternaria alternata as compared to LPS, a metabolic shift in cDCs caused a significant accumulation of the TCA cycle metabolites alpha ketoglutarate and succinate, but a decrease in fumarate and malate. Following this we found that upon alternaria stimulation, both succinate and alpha ketoglutarate administration were able to rescue the inhibition of Tfh13s observed with glutaminase I inhibition. Other T cell subsets were unaffected. Conclusion This finding illustrates the role of glutamine-derived metabolites in the polarization of T-cells. Funding Source NHLB1-NIH (RO1HL162991) to RKM Topic Categories Immediate Hypersensitivity, Asthma, and Allergic Responses (HYP)