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. 2020 Mar 4;217(5):e20190472. doi: 10.1084/jem.20190472

Figure 8.

Figure 8.

Models of the regulation of IgE CSR. (A) Our data indicate that while IL-4 promotes both IgE and IgG1 CSR, IL-21 inhibits IgE CSR but promotes IgG1 CSR. IL-21 appears to be the key negative regulator of IgE under a broad range of conditions in both mouse and human B cells. We observed that IFN-γ was required for IgG2a/c CSR but in vivo had no physiological impact on IgE and IgG1 CSR under the conditions tested. (B) Model of the interaction of a T cell (such as a Tfh cell) with a B cell. Our data indicate that IL-21 produced by T cells, signaling via the IL-21R and STAT3 in B cells, inhibits IgE germline transcription, thereby preventing IgE CSR. Conversely, IL-4, signaling via the IL-4R and STAT6; and CD40L, signaling via CD40 and NF-κB; are known to directly promote IgE germline transcription in B cells (Geha et al., 2003). The model does not exclude the possibility that other signaling pathways downstream of these receptors may also contribute to IgE regulation. The hatched lines show an expanded view of the regulation of IgE germline transcription by these receptors in C. (C) Model of the regulation of IgE germline transcription by the relative strength of IL-4R, CD40, and IL-21R signaling in B cells. Quantitative differences in signals from these receptors may depend on the extent and/or duration of receptor ligation (such as differences in the relative amounts of IL-4, IL-21, and CD40L expressed by T cells, versus the duration of T cell–B cell contacts). Three cases are provided for consideration: (1) IgE germline transcription is promoted in the context of strong IL-4R and CD40 signals. The CD40 signals attenuate the inhibitory signals downstream of the IL-21R. (2) When CD40 signals are weaker, strong IL-21R signals can inhibit IgE germline transcription, even in the presence of strong IL-4R signals. (3) When IL-4R signals are too weak, only minimal IgE germline transcription would occur regardless of the relative strength of CD40 and IL-21R signals. Note that in all three cases, IgG1 germline transcription would be promoted by these signals, and thus cases 2 or 3 would lead to a bias toward IgG1 CSR rather than IgE CSR.