Differential Expression of the Adaptor Protein HSH2 Controls the Quantitative and Qualitative Nature of the Humoral Response

摘要

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 mice. Constitutive expression of HSH2 in the B lineage at levels comparable to B1a/b 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 decreased by approximately 80–90% compared to control mice. Analysis of HSH2 Tg B cell activation in vitro demonstrated that HSH2 selectively regulates the B cell response to TNF family receptors (i.e. CD40 and BAFF-R), but not BCR- or TLR-dependent signals. These data demonstrate that changes in HSH2 expression have profound effects on the humoral immune response.