STAT5b dimers and tetramers are critical for Mast Cell Function

Abstract

Abstract Signal transducers and activators of transcription (STATs) are latent transcription factors vital for lymphoid, myeloid, and erythroid cell development, survival, proliferation, and function. Activated STATs form dimers that translocate to the nucleus and bind high affinity STAT DNA motifs to modulate gene expression. We previously found that Stat5b is required for IgE-mediated mast cell cytokine production in vitro. In this study, we found that STAT5b KO mice demonstrate decreased sensitivity to IgE-mediated passive systemic anaphylaxis (PSA) and reduced cytokine production in vivo. This is not due to differences in mast cell numbers or distribution. Interestingly, STAT5b KO mice exhibit elevated levels of serum IgE that could diminish PSA by preventing binding of antigen-specific IgE. Increased serum IgE is not tied to changes in B cell number or their ability to produce IgE in vitro. In addition to dimers, activated STAT proteins can also form tetramers through an oligomerization process once dimers bind to tandem low-affinity STAT DNA motifs. Similar to STAT5bKO, in vitro IgE-mediated cytokine production is decreased in Stat5a-Stat5b double knock-in (DKI) mice in which STAT5 proteins can form dimers but not tetramers. In vivo, DKI mice exhibit decreased PSA sensitivity, with no difference in mast cell numbers or distribution, and a modest increase in serum IgE. Collectively, these data illuminate the unique and specific roles of STAT5 dimers and tetramers in mast cell function and allergic disease.