Spatiotemporal regulation of HSH2 expression is critical for the humoral immune response.

Abstract

The adaptor protein HSH2 has been shown to be dynamically expressed in cells of the B lineage. HSH2 is upregulated in response to TLR agonists and stimulation through the TNF family receptors CD40 and BAFF‐R in vitro. In mice challenged with T‐dependent antigen, HSH2 is expressed exclusively in the light zone of germinal centers. To address the function of HSH2, transgenic mice were generated resulting in the constitutive expression of HSH2 in all cells of the B lineage. These mice display a mild B cell developmental defect manifest by a delay in population of the peripheral B cell pool and reduction of late transitional populations. BrdU labeling demonstrated a reduced efficiency of B cell maturation in the periphery; however the B cell compartment of adult HSH2 Tg mice is relatively normal. The serum Ig titers of HSH2 Tg mice, however, are reduced in comparison to wild type. In addition, HSH2 Tg animals exhibited a significant impairment in their response to immunization with both T‐independent and T‐dependent antigens. B cells isolated from HSH2 Tg animals fail to respond normally to stimulation through BAFF‐R and CD40 receptors although their response to TLR agonists is unaffected. These data suggest that regulation of HSH2 expression is critical for normal B cell responses to signals delivered via receptors of the TNF family thereby controlling the humoral immune response.