STAT3 couples with 14-3-3σ to regulate BCR signaling, B cell differentiation, and IgE production.

Abstract Background STAT3 or Dock8 loss-of-function mutations cause HIES and the role of abnormal T cell function has been extensively investigated, however the contribution of B cell intrinsic dysfunction to elevated IgE levels is unclear. Objective We sought to determine the underlying molecular mechanism of how STAT3 regulates BCR signaling, B cell differentiation, and IgE production. Methods We used samples from STAT3 loss-of-function (LOF) patients and samples from Mb1Cre stat3flox/flox mice (B-STAT3 KO) to investigate the mechanism of HIES. Results We found that the peripheral B cell homeostasis in B-STAT3 KO mice mimicked the phenotype of STAT3 LOF patients, having decreased follicular (FO) and germinal center (GC) B cells, but increased marginal zone (MZ) and IgE+ B cells. Furthermore, B-STAT3 KO B cells had reduced B cell receptor (BCR) signaling upon antigenic stimulation due to reduced BCR clustering and decreased accumulation of WASP and F-actin. Excitingly, a central hub protein, 14-3-3σ, which is essential for the increase in IgE production, was enhanced in B cells of B-STAT3 KO mice and STAT3 LOF patients. The increase of 14-3-3σ was associated with increased expression of the upstream mediator, miRNA146A. The inhibition of 14-3-3σ with R18 peptide in B-STAT3 KO mice rescued the BCR signaling, FO, GC, and IgE+ B cell differentiation to the degree of wild-type (WT) mice. Conclusions Altogether, our study has established a novel regulatory pathway of STAT3-miRNA146A-14-3-3σ to regulate BCR signaling, peripheral B cell differentiation and IgE production.