Endogenous expression of the adaptor protein HSH2 is regulated in a dynamic manner during B cell maturation and differentiation. Developing B cells lack detectable HSH2, whereas T1 and T2 B cells in the periphery exhibit increasing levels of expression. Mature follicular B cells exhibit decreased expression of HSH2 compared to T2 cells and expression is further downregulated in germinal center B cells. In contrast, marginal zone B cells and B1a/b B cells exhibit high-level HSH2 expression. Regulation of HSH2 expression plays a critical role in determining the outcome of the humoral immune response as demonstrated using HSH2 transgenic (Tg) and HSH2 hypomorph (HSH2-Lo) mice. Constitutive expression of HSH2 in B cells results in decreased serum Ig titers for all subclasses with the exception of IgA. HSH2-Tg mice immunized with T-dependent or T-independent antigens exhibit a moderate decrease in the production of antigen-specific IgM, whereas class switched isotypes are significantly decreased compared to control mice. In contrast, HSH2-Lo mice exhibit accelerated and enhanced class switching in response to challenge with antigen. Analysis of HSH2 Tg versus HSH2-Lo B cell activation in vitro demonstrated that altered HSH2 expression does not affect class switching, but it does lead to altered expression of the transcriptional regulatory proteins Bach2 and Blimp-1. Thus, HSH2 appears to play an important role in regulating terminal differentiation of B cells.
- Copyright © 2013 by The American Association of Immunologists, Inc.