STAT5B AND STAT5 TETRAMERS ARE ESSENTIAL FOR IGE-MEDIATED MAST CELL FUNCTION

Signal Transducers and Activators of Transcription (STATs) are latent transcription factors that mediate several cellular responses. This protein family consists of seven members, STAT1 – 6 including two closely related molecules, STAT5a and STAT5b, that show 96% amino acid sequence homology and are critical for lymphoid, myeloid and erythroid cell development and function. Activated STAT proteins dimerize and translocate to the nucleus, where they bind to high-affinity DNA motifs to modulate gene expression. We recently identified STAT5b as the critical regulator of IgE-mediated cytokine production in mast cells. STAT5b knockout (KO) cells show decreased sensitivity to IgE-mediated passive systemic anaphylaxis accompanied with decreased production of IL-6 and IL-13 compared to wild type counterparts. Interestingly, STAT5b KO mice demonstrated elevated levels of serum IgE but a normal response to histamine-mediated passive systemic anaphylaxis. The current work demonstrates that STAT5b regulates mast cell function both in vivo and in vitro. Additionally, activated STAT proteins can also form tetramers through an N-terminal domain-mediated oligomerization process when bound to low-affinity tandem motifs. Dr. Warren Leonard’s laboratory generated STAT5a-STAT5b double knock-in (DKI) mice in which STAT5 proteins are phosphorylated and can form dimers but not tetramers. We have now found that bone marrow-derived mast cells from STAT5 DKI mice are defective in IgE-induced cytokine and chemokine production and exhibit defective stem cell factor (SCF)-induced migration and survival responses in vitro. Similarly, IgE-mediated passive systemic anaphylaxis is decreased in STAT5 DKI mice. These data indicate that Stat5 tetramers are critical for some aspects of mast cell function in allergic and inflammatory disease

Controlling Mast Cell Activation and Homeostasis: Work Influenced by Bill Paul That Continues Today

Mast cells are tissue resident, innate immune cells with heterogenous phenotypes tuned by cytokines and other microenvironmental stimuli. Playing a protective role in parasitic, bacterial, and viral infections, mast cells are also known for their role in the pathogenesis of allergy, asthma, and autoimmune diseases. Here, we review factors controlling mast cell activation, with a focus on receptor signaling and potential therapies for allergic disease. Specifically, we will discuss our work with FcεRI and FγR signaling, IL-4, IL-10, and TGF-β1 treatment, and Stat5. We conclude with potential therapeutics for allergic disease. Much of these efforts have been influenced by the work of Bill Paul. With many mechanistic targets for mast cell activation and different classes of therapeutics being studied, there is reason to be hopeful for continued clinical progress in this area