Regulation of B cell fate by chronic activity of the IgE B cell receptor

Abstract

IgE can trigger potent allergic responses, yet the mechanisms regulating IgE production are poorly understood. Here we reveal that IgE+ B cells are constrained by chronic activity of the IgE B cell receptor (BCR). In the absence of cognate antigen, the IgE BCR promoted terminal differentiation of B cells into plasma cells (PCs) under cell culture conditions mimicking T cell help. This antigen-independent PC differentiation involved multiple IgE domains and Syk, CD19, BLNK, Btk, and IRF4. Disruption of BCR signaling in mice led to consistently exaggerated IgE+ germinal center (GC) B cell but variably increased PC responses. We were unable to confirm reports that the IgE BCR directly promoted intrinsic apoptosis. Instead, IgE+ GC B cells exhibited poor antigen presentation and prolonged cell cycles, suggesting reduced competition for T cell help. We propose that chronic BCR activity and access to T cell help play critical roles in regulating IgE responses.Antibodies are proteins that recognize and bind to specific molecules, and so help the immune system to defend the body against foreign substances that are potentially harmful. In some cases, harmless substances – such as pollen, dust or food – can trigger this response and lead to an allergic reaction. A type of antibody called immunoglobulin E (IgE) is particularly likely to trigger an allergic response.In general, immune cells called plasma cells produce antibodies and release them into the body. However, in B cells – the cells from which plasma cells develop – the antibodies remain on the surface of the cells. Here, the antibody acts as a “receptor” that allows the B cell to tell when its antibody has bound to a specific substance.Generally, B cells only activate when their B cell receptors bind to a specific substance. This binding triggers signals inside the cell that determine its fate – such as whether it will develop into a plasma cell. Recent studies have shown that B cells that have IgE on their surface (IgE+ B cells) are predisposed to develop rapidly into plasma cells.To investigate why this is the case, Yang et al. have now studied B cells both in cell culture and in mice. The results show that the IgE B cell receptor autonomously signals to the cell even when it is not bound to a specific substance, in a manner that differs from other types of B cell receptors. This increases the likelihood that the IgE+ B cell will develop into a plasma cell and limits the competitive fitness of IgE+ B cells. These findings provide new insights into how IgE responses are regulated by the B cell receptor.The next step will be to determine, at a molecular level, the basis for the autonomous signaling produced by the IgE B cell receptor when it is not bound to a specific substance. It will then be possible to investigate how this mechanism compares with the way that signals are normally transmitted when a B cell receptor binds to a specific substance.