Abstract
Abstract Members of the disintegrin and metalloprotease (ADAM) family can regulate lymphocyte development and function by cleaving membrane receptors. Previous studies showed that ADAM10 cleaves the B cell receptors, CD23 and Notch2, in vitro. However, in the absence of in vivo models, the physiologic impact of these events has not been examined. Thus, we generated B cell-specific ADAM10 KO and transgenic (Tg) mice to determine the role of ADAM10 in B cell development and function. Notch signaling regulates the differentiation of common lymphoid progenitors (CLPs) by promoting T cell fate. Accordingly, overexpression of ADAM10 in CLPs completely blocked B cell development. Deletion of ADAM10 from B cells in ADAM10fl/fl, CD19-cre+ mice prevented differentiation of marginal zone B cells, which is dependent on Notch2 signaling. In addition, expression of CD23 on ADAM10null B cells was dramatically elevated while levels of soluble CD23 were reduced in serum. As a result, IgE production by ADAM10fl/fl, CD19-cre+ mice was remarkably suppressed upon immunization, mimicking the response of CD23Tg mice. Finally, production of IgG1 and IgG2b was profoundly inhibited, suggesting a novel role for ADAM10 in class-switching to IgG. These results illustrate the physiologic role of ADAM10 in Notch signaling and CD23 cleavage. Moreover, they identify ADAM10 as a critical regulator of B cell development and immunoglobulin production. AHA 0815066E, NIAID R01AI18697, NIAID U19AI077435
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