HIF-2α plays a critical role in developing pathogenic Th2 cells for steroid-ressitant allergic inflammation 3482

Abstract Description Allergen-specific memory Th2 (mTh2) cells are critical in relapses of asthma following allergen re-exposure. Additionally, IL-33 released from damaged epithelial cells, promotes steroid-resistant type 2 inflammation by activating CD44hiST2hiCD4 T cells. Thus, we hypothesized that steroid-resistant pathogenic Th2 cells develop from allergen-specific mTh2 cells in the IL-33-rich lung environments. To test this hypothesis, we generated allergen-specific memory CD4 T cells from naïve T cells in mice and treated these mice with IL-33, allergen, or both. We found that inflammation became steroid-resistant only in the group challenged with a mixture of allergen and IL-33. To investigate underlying mechanisms, we performed single-cell transcriptome analysis of allergen-specific CD4 T cells and identified Th2 cluster, in which transcription factors such as Epas1 were significantly upregulated in steroid-resistant challenge compared to steroid-sensitive. Overexpressing HIF-2α encoded by Epas1 in Th2 cells induced steroid resistance, while its genetic deficiency restored steroid sensitivity. Moreover, mice treated with Belzutifan, an FDA-approved HIF-2α antagonist, developed steroid-sensitive allergic inflammation regardless of the challenge. Altogether, we propose that HIF-2α plays a crucial role in the function of pathogenic Th2 cells and their steroid insensitivity for developing steroid-resistant allergic inflammation. Corresponding author: Yong Woo Jung, [email protected] Funding Sources This research was supported by the National Research Foundation of Korea (NRF) through funding from the Ministry of Education, Science and Technology (NRF-2019R1A6A1A03031807, NRF-2021R1A2C2004279, and NRF-00222762). Topic Categories Lymphocyte Differentiation and Peripheral Maintenance (LYM)