Control of the STAT6–BCL6 Antagonism by SWAP-70 Determines IgE Production

Abstract

Asthma and allergies are major health concerns in which Ig isotype E plays a pivotal role. Ag-bound IgE drives mast cells and basophils into exocytosis, thereby promoting allergic and potentially anaphylactic reactions. The importance of tightly regulated IgE production is underscored by severe immunological conditions in humans with elevated IgE levels. Cytokines direct IgH class-switching to a particular isotype by initiation of germline transcription (GLT) from isotype-specific intronic (I) promoters. The switch to IgE depends on IL-4, which stimulates GLT of the Iε promoter, but is specifically and strongly impaired in Swap-70−/− mice. Although early events in IL-4 signal transduction (i.e., activation of the JAK/STAT6 pathway) do not require SWAP-70, SWAP-70 deficiency results in impaired Iε GLT. The affinity of STAT6 to chromatin is reduced in absence of SWAP-70. Chromatin immunoprecipitation revealed that SWAP-70 binds to Iε and is required for association of STAT6 with Iε. BCL6, known to antagonize STAT6 particularly at Iε, is increased on Iε in absence of SWAP-70. Other promoters bound by BCL6 and STAT6 were found unaffected. We conclude that SWAP-70 controls IgE production through regulation of the antagonistic STAT6 and BCL6 occupancy of Iε. The identification of this mechanism opens new avenues to inhibit allergic reactions triggered by IgE.

Regulation of age-associated B cells by IRF5 in systemic autoimmunity

“…The enrichment of IRF motifs in DKO ABC peaks was mechanistically linked to increased IRF5 activity due to lack of the inhibitory effects of the SWEF proteins. Both DEF6 and SWAP-70 are found in the nucleus 32 , 42 suggesting that they inhibit the activity of nuclear IRF5, a finding supported by our biochemical studies. Given their ability to bind to the IAD of IRF5 they could also potentially interfere with its cross-talk with AP-1 proteins 14 .…”

Regulation of systemic autoimmunity and CD11c + Tbet + B cells by SWEF proteins

“…Nuclear SWAP-70 was originally postulated to be a central player in class switch recombination. As such, SWAP-70 was initially discovered in a screen aimed at identifying proteins involved in mediating class switch recombination [8] and was subsequently shown to directly bind to the Iε promoter in IL-4 stimulated B cells and to promote switching to IgE by regulating the STAT6-BCL6 antagonism [44]. Consistent with these observations, mice deficient in SWAP-70 exhibit selective impairments in IgE responses while producing relatively normal levels of other isotypes [45], suggesting that SWAP-70 plays a unique role in the control of IgE production.…”

B Cell Intrinsic Mechanisms Constraining IgE Memory

“…The Iε promoter binds E2A, AP1, C/EBP, STAT6, PU.1, Pax5, and NF-κB ( 28 , 29 ). Classically, Iε-Sε transcription before IgE CSR is induced by phosphorylation and dimerization of STAT6, which is stabilized by SWAP-70 ( 30 ). While IL4 induces STAT6 and NFIL3/E4BP4, CD40 ligation synergistically activates NF-κB ( 31 ).…”