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A mutation in STAT3 has been linked to the incidence of autosomal dominant hyper IgE syndrome, a disease characterized by elevated serum IgE Ab. However, how this genetic mutation leads to the phenotype has not been fully understood. We investigated the specific role of STAT3 in the germinal center (GC) B cells and plasma cells for IgE class switching. Through the use of STAT3 conditional knockout (cKO) mice in a Th2-type immunization model, we demonstrated that CD2-Cre-driven STAT3 cKO mice showed elevated IgE and decreased IgG 1 in the serum and a reduction in GC formation. Within the GC, IgG 1  + GC B cells were decreased, whereas IgE + GC B cells were more prevalent. Additionally, these mice exhibited reduced IgG 1 and elevated IgE populations of Ab-producing plasma cells. Subsequent experiments using a CD19-Cre cKO mouse established this effect to be B cell-intrinsic. Transcription factors critical for GC and plasma cell differentiation, including Bcl-6 and Aicda , were shown to function as downstream signals of STAT3 regulation. Chromatin immunoprecipitation sequencing analysis revealed that many genes, including Bcl3 and Crtc2 , were among the direct STAT3 regulated targets. Mice with STAT3 deficiency in B cells also demonstrated an increase in lung inflammation when used in an asthma-like disease model. This model suggests a negative role for STAT3 in regulating class switching of the GC B cells from the IgG 1 to the IgE producing state, which may serve as a therapeutic target for treatment of autosomal dominant hyper IgE syndrome and other immune disorders.

Transcription Factor STAT3 Serves as a Negative Regulator Controlling IgE Class Switching in Mice