Stimuli that enhance IgA class switching increase histone 3 acetylation at Sα, but poorly stimulate sequential switching from IgG2b

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Abstract
Germ‐line (GL) α transcription can be induced in mouse splenic B cells by LPS and TGF‐β. This stimulation results in ∼1% IgA+ cells, which can be increased by IL‐4, IL‐5, and anti‐IgD dextran (αδDex). To determine the mechanism of this increase, we asked whether IgA class switching correlates with acetylation of histone 3 at Sα, the switch region for IgA. In the presence of the survival factor B lymphocyte stimulator (BLyS), acetylated histone 3 (AcH3) at Sα was changed little by TGF‐β in LPS‐stimulated mouse splenic B cell cultures, despite induction of GLα RNA. Compared with BLyS/LPS/TGF‐β alone, treatment with BLyS/LPS/TGF‐β/IL‐4/IL‐5/αδDex increased AcH3 at Sα fourfold, and also increased GLα RNA levels more than eightfold. By contrast, IgG2b class switching was optimal in BLyS/LPS/TGF‐β alone, and was suppressed by IL‐4/IL‐5/αδDex. Thus, B cell activators that increase IgA class switching do not increase IgG2b class switching. Further investigation showed that in contrast to purified IgM+ cells, IgG2b+ cells switched poorly to IgA in response to BLyS/LPS/TGF‐β/IL‐4/IL‐5/ ± αδDex. These results suggest that IgA class switching is unusual among isotypes in its requirement for multiple B cell activation signals in addition to LPS and the cytokine that initiates the corresponding GL transcription.