“Cannabinoid receptor type 2 (CB₂) is the primary receptor pathway mediating the immunologic consequences of cannabinoids. We recently reported that human peripheral blood B cells express CB₂ on both the extracellular membrane and at intracellular sites, where-as monocytes and T cells only express intracellular CB₂. To better understand the pattern of CB₂ expression by human B cells, we examined CD20⁺ B cells from three tissue sources. Both surface and intracellular expression were present and uniform in cord blood B cells, where all cells exhibited a naïve mature phenotype (IgD⁺/CD38^Dim). While naïve mature and quiescent memory B cells (IgD^–/CD38^–) from tonsils and peripheral blood exhibited a similar pattern, tonsillar activated B cells (IgD^–/CD38⁺) expressed little to no surface CB₂. We hypothesized that regulation of the surface CB₂ receptor may occur during B cell activation. Consistent with this, a B cell lymphoma cell line known to exhibit an activated phenotype (SUDHL-4) was found to lack cell surface CB₂ but express intracellular CB₂. Furthermore, in vitro activation of human cord blood resulted in a down-regulation of surface CB₂ on those B cells acquiring the activated phenotype but not on those retaining IgD expression. Using a CB₂ expressing cell line (293 T/CB₂-GFP), confocal microscopy confirmed the presence of both cell surface expression and multifocal intracellular expression, the latter of which co-localized with endoplasmic reticulum but not with mitochondria, lysosomes, or nucleus. Our findings suggest a dynamic multi-compartment expression pattern for CB₂ in B cells that is specifically modulated during the course of B cell activation.”