GATA-1 regulates the generation and function of basophils

Significance The GATA-1 transcription factor has been extensively characterized and shown to play crucial roles in the development of erythroid cells, magakaryocytes, eosinophils, and mast cells. However, the role of GATA-1 in basophils remained unidentified. We demonstrate that knockdown of Gata1 gene expression in basophils results in impaired cytokine production upon allergen-mediated activation. Moreover, ΔdblGATA mice carrying the mutated Gata1 promoter have reduced numbers of basophils and their progenitors and show impaired responses in basophil-mediated protective immunity against parasitic infections. Thus, GATA-1 plays an important role in both generation and activation of basophils, and ΔdblGATA mice display numerical and functional aberrancy in basophils, in addition to the well-known eosinophil deficiency. Developmental processes of hematopoietic cells are orchestrated by transcriptional networks. GATA-1, the founding member of the GATA family of transcription factors, has been demonstrated to play crucial roles in the differentiation of erythroid cells, magakaryocytes, eosinophils, and mast cells. However, the role of GATA-1 in basophils remains elusive. Here we show that basophils abundantly express Gata1 mRNAs, and that siRNA-mediated knockdown of Gata1 resulted in impaired production of IL-4 by basophils in response to the stimulation with IgE plus antigens. ΔdblGATA mice that carry the mutated Gata1 promoter and are widely used for functional analysis of eosinophils owing to their selective loss of eosinophils showed a decreased number of basophils with reduced expression of Gata1 mRNAs. The number of basophil progenitors in bone marrow was reduced in these mice, and the generation of basophils from their bone marrow cells in culture with IL-3 or thymic stromal lymphopoietin was impaired. ΔdblGATA basophils responded poorly ex vivo to stimulation with IgE plus antigens compared with wild-type basophils as assessed by degranulation and production of IL-4 and IL-6. Moreover, ΔdblGATA mice showed impaired responses in basophil-mediated protective immunity against intestinal helminth infection. Thus, ΔdblGATA mice showed numerical and functional aberrancy in basophils in addition to the known deficiency of eosinophils. Our findings demonstrate that GATA-1 plays a key role in the generation and function of basophils and underscore the need for careful distinction of the cell lineage responsible for each phenotype observed in ΔdblGATA mice.