HIF1α regulates Tfr induction that restrains Tfh13 polarization in a murine model of allergy
Presentation Time: 11:30 AM - 12:45 PM
Poster Board Number: B863
Abstract ID: 5365
Presenting Author:
Maria Del Carmen Camarena , Graduate Student at Virginia Commonwealth Univ. Sch. of Med., Massey Comp. Cancer Ctr., Virginia Commonwealth Univ.
Abstract:
Allergic asthma is a chronic inflammatory disease affecting the lungs, which is mediated by allergen-specific IgE and type 2 cytokines. Tfh13 cell polarization is important for induction of allergen-specific IgE from B cells. Tfr cells have been shown to restrain Tfh13 polarization. Our lab has shown that polarization of these T cell subsets is directed by conventional type 2 dendritic cells (cDC2). Our previous studies show that cDC2s sensitized with Alternaria alternata, a fungal allergen, carry a distinct metabolic profile reliant upon glutaminolysis with a marked increase in the TCA metabolite alpha-ketoglutarate (α-KG). α-KG is a substrate of hypoxia-inducible factor prolyl hydroxylase domains (PHDs). Excess α-KG drives PHD degradation of hypoxia-inducible factor 1α (HIF1α). Our studies have shown use of a glutaminase I (GLS1) specific inhibitor, CB-839, results in decreased α-KG and increased HIF1α in Alternaria-sensitized cDC2s as compared to vehicle controls. Additionally, mice intranasally treated with the HIF1α stabilizing drug, Roxadustat, show an increase in Tfr cells, with a corresponding reduction in Tfh13s and IgE+ B cells. Finally, in a murine model of allergic asthma, treatment with Roxadustat reduced airway hyperresponsiveness compared to vehicle control. Our results support a model where downstream gene expression induced by HIF1a may be necessary for the induction of Tfh13-restraining Tfr cells.
HIF1α regulates Tfr induction that restrains Tfh13 polarization in a murine model of allergy
Category
Poster and Podium (Block Symposium)