title: Differential expression of the adaptor protein HSH2 controls the quantitative and qualitative nature of the humoral response.
abstract: Endogenous expression of the adaptor protein hematopoietic Src homology 2-containing adaptor protein (HSH2) is regulated in a dynamic manner during B cell maturation and differentiation. Developing B cells lack detectable HSH2, whereas transitional 1 and 2 B cells in the periphery exhibit increasing levels of expression. Mature follicular B cells exhibit decreased expression of HSH2 compared with transitional 2 B 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) 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 Ags exhibit a moderate decrease in the production of Ag-specific IgM, whereas class-switched isotypes are decreased by ∼80-90% compared with 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.
authors.affiliation: Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: R Glenn
authors.initials: RG
authors.lastname: King
authors.forename: Brantley R
authors.initials: BR
authors.lastname: Herrin
authors.forename: Louis B
authors.initials: LB
authors.lastname: Justement
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D015153:Blotting, Western; D002454:Cell Differentiation / Q000276:immunology*; D002469:Cell Separation; D005434:Flow Cytometry; D018858:Germinal Center / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D056724:Immunity, Humoral / Q000276:immunology*; D038041:Lymphopoiesis / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C509871:HSH2 protein, mouse