Cannabinoid receptor 2 plays a critical role in marginal zone B cell retention and T-independent humoral responses (45.6)

Abstract

Abstract Marginal zone (MZ) B cells play a very important role in the early defense against blood borne pathogens by producing natural IgM and inducing T-independent (TI) humoral responses. Lack of MZ B cells has been associated with higher susceptibility to bacterial infections. However, the development/maintenance of these cells is not fully understood. Mice deficient in cannabinoid receptor (CB) 2, a Gi protein-coupled receptor highly expressed on B cells, showed a significant reduction in MZ B cells. We found that CB2 deficiency correlated with significantly decreased natural and TI IgM levels (post-immunization) in CB2-/- mice. We investigated the mechanism by which CB2 regulates MZ B cell numbers. Analysis of mixed BM chimeras showed a B cell intrinsic CB2 requirement, although additional data suggested no involvement of CB2 in MZ B cell development or survival. We next studied whether CB2 regulates MZ B cell adhesion/retention. Interestingly, WT B cells showed significantly higher adhesion to ICAM-1+VCAM-1, critical for MZ B cell retention in the splenic MZ, compared to CB2-/-. 2-AG, an endogenous CB2 ligand further enhanced WT B cell adhesion and blocking of CB2 signaling in WT mice with a CB2-antagonist dislodged MZ B cells from the spleen, increasing their numbers in the blood. Unmanipulated CB2-/- mice also exhibited increased MZ B cells in the blood compared to WT. Collectively, our study identifies a crtical role of CB2 in MZ B cell retention and TI humoral responses.