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Regulation of Cell Surface CB2 Receptor during Human B Cell Activation and Differentiation

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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+/CD38Dim). 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.

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Research reported in this publication was supported by the National Institute on Drug Abuse, National Institutes of Health, under award numbers 5-R01-DA037102. JT Castaneda was supported by a Ruth L. Kirschstein National Research Service Award (NRSA) Individual Predoctoral Fellowship to Promote Diversity in Health-Related Research from the National Institute on Drug Abuse, National Institutes of Health, under award numbers 1 F31 DA036293 and by a North American Graduate Fellowship Award from the American College of Toxicology. Flow cytometry was performed in the UCLA Jonsson Comprehensive Cancer Center (JCCC) and Center for AIDS Research (CFAR) Flow Cytometry Core Facility that is supported by National Institutes of Health awards CA-16042 and AI-28697, and by the JCCC, the UCLA AIDS Institute, and the David Geffen School of Medicine at UCLA. Confocal laser scanning microscopy was performed at the CNSI Advanced Light Microscopy/Spectroscopy Shared Resource Facility at UCLA, supported with funding from NIH-NCRR shared resources grant (CJX1-443835-WS-29646) and NSF Major Research Instrumentation grant (CHE-0722519). Cord blood mononuclear cells derived from anonymized donors were obtained from the CFAR Virology Core Lab that is supported by the National Institutes of Health Award AI-28697 and by the UCLA AIDS Institute and the UCLA Council of Bioscience Resources.

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Correspondence to Michael D. Roth.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Castaneda, J.T., Harui, A. & Roth, M.D. Regulation of Cell Surface CB2 Receptor during Human B Cell Activation and Differentiation. J Neuroimmune Pharmacol 12, 544–554 (2017).

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