Regulation of B cell differentiation by the adaptor protein HSH2 (87.53)

Abstract

Abstract The adaptor protein HSH2 is selectively expressed at low basal levels in cells of the B lineage. However, stimulation of B cells via CD40, BAFF-R, TLR4 and TLR9 upregulates HSH2 expression within 6–12 h in a NF-kB-dependent manner. Thus, it was hypothesized that HSH2 may regulate B cell survival and/or differentiation. HSH2 transgenic (Tg) mice were generated that constitutively express HSH2 in cells of the B lineage to determine if HSH2 causes gross changes in B cell subpopulations or functional responses. No changes were observed in developing B cell subpopulations in the bone marrow and the peripheral B cell compartment appeared normal with the exception of a 50% decrease in marginal zone B cells. Analysis of serum Ig levels in HSH2 Tg mice revealed a 40–50% decrease in IgM, a 20% decrease in IgA and a 70–85% decrease in other class switched isotypes compared to control animals. HSH2 Tg mice exhibited a significant impairment in their response to immunization with T-independent type 1 and 2 antigens and exhibited a similar defect in their 1° and 2° response to T-dependent antigen. Constitutive HSH2 expression was not observed to alter BCR-mediated signaling. In contrast, HSH2 Tg B cells exhibited defective responses to CD40 and BAFF-R signaling in vitro, but responded normally to TLR agonists. Thus, HSH2 appears to be important for selectively regulating the B cell functional response to CD40 and BAFF-R signaling.