The transcription factor NFIL3/E4BP4 regulates the developmental stage-specific acquisition of basophil function

Background: Basophils are rare but important effector cells in many allergic disorders. Contrary to their early progenitors, the terminal developmental processes of basophils in which they gain their unique functional properties are unknown. Objective: We sought to identify a novel late -stage basophil precursor and a transcription factor regulating the terminal maturation of basophils. Methods: Using flow cytometry, transcriptome analysis, and functional assays, we investigated the identification and functionality of the basophil precursors as well as basophil development. We generated mice with basophil-specific deletion of nuclear factor IL -3 (NFIL3)/E4BP4 and analyzed the functional impairment of NFIL3/E4BP4-deficient basophils in vitro and in vivo using an oxazolone-induced murine model of allergic dermatitis. Results: We report a new mitotic transitional basophil precursor population (referred to as transitional basophils) that expresses the Fc epsilon RIa chain at higher levels than mature basophils. Transitional basophils are less responsive to IgElinked degranulation but produce more cytokines in response to IL -3, IL -33, or IgE cross -linking than mature basophils. In particular, we found that the expression of NFIL3/E4BP4 gradually rises as cells mature from the basophil progenitor stage. Basophil-specific deletion of NFIL3/E4BP4 reduces the expression of genes necessary for basophil function and impairs IgE receptor signaling, cytokine secretion, and degranulation in the context of murine atopic dermatitis. Conclusions: We discovered transitional basophils, a novel latestage mitotic basophil precursor cell population that exists between basophil progenitors and postmitotic mature basophils. We demonstrated that NFIL3/E4BP4 augments the IgE-mediated functions of basophils, pointing to a potential therapeutic regulator for allergic diseases. (J Allergy Clin Immunol 2024;153:132-45.)