Mice deficient for paired immunoglobulin (Ig)-like receptor B (PIR-B) show defective regulation of receptor-mediated activation in antigen-presenting cells. Older PIR-B-/- mice had an increased number of peritoneal BI cells. Splenic PIR-B-/- B2 cells were constitutively activated and proliferated much more than those from wild-type mice upon B cell receptor ligation. T helper type 2 (TH2)-prone humoral responses were augmented in PIR-B-/- mice upon immunization with T-dependent antigens, including increased interleukin 4 and decreased interferon-γ responses, as well as enhanced IgGI and IgE production. Impaired maturation of dendritic cells (DCs), possibly due to perturbed intracellular signaling, was responsible for the skewed responses. Thus, PIR-B is critical for B cell suppression, DC maturation and for balancing THI and TH2 immune responses.