Identification of a novel basophil precursor cell and the transcription factor NFIL3/E4BP4 regulating basophil function

Abstract

Basophils are very rare granulocytes in the body but not negligible mediating the type 2 immune responses in asthma and allergic diseases. Previous reports showed that basophils mature in the bone marrow from the hematopoietic stem cells. However, little has been known about basophil development other than basophil progenitor cells (BaPs). Here, I report a novel basophil precursor population that expresses glycoprotein CD200 receptor 3 (CD200R3) and IgE receptor FcRI alpha chain at high levels. I found that the novel precursor cells can be differentiated from BaPs and into mature basophils in vitro and in vivo, thus I termed them ‘pre-basophils (pre-Basos)’. Remarkably, I found that pre-Basos are still mitotic and inferior in degranulation mediated by IgE-crosslinking, but produce type 2 cytokines in response to IL-3 or IL-33 very robustly compared to mature basophils. Furthermore, IL-3 treatment induced the production of IL-4 and IL-13 whereas IL-33 triggered IL-13, but not IL-4 production. The transcriptome analysis of BaPs, pre-Basos, and mature basophils revealed the differentially expressed genes (DEGs) defining the precursor cells and controlling their functions. By using basophil-specific deletion of transcription factor NFIL3/E4BP4, one of the up-regulating DEGs, I demonstrated that NFIL3 has a suppressive role in IgE-receptor signaling, cytokine production, and degranulation both in vitro and in vivo in the setting of murine allergic diseases. I demonstrated that basophil-specific deletion of NFIL3 reduces the expression of genes required for basophil function. Collectively, the study determines a new basophil precursor population that exerts unprecedented responsiveness and dichotomy in cytokine-induced cytokine production and will help in understanding the basophil biology governing various type 2 immune responses.