The splenic marginal zone (MZ) is located at the border of the white pulp and red pulp. The arterial circulation of the spleen terminates in a porous vascular sinus, the marginal sinus, which lies in the MZ. Blood from the marginal sinus then transits through the MZ and into the red pulp (Mebius and Kraal, 2005
). The MZ contains specialized macrophages, B cells, and dendritic cells. Cells in the MZ are continuously exposed to antigens carried in the blood (Mebius and Kraal, 2005
MZ B cells differ from follicular B cells in several ways. Murine MZ B cells do not recirculate; they have a partially activated phenotype that allows for quick and vigorous antibody responses to blood-borne antigens and they are able to self-renew (Martin and Kearney, 2002
). Additionally, MZ B cells differ from follicular B cells immunophenotypically by high surface expression of IgM, the complement receptor CD21, and the nonclassical major histocompatibility complex I molecule CD1d that allows for presentation of lipid antigens (Pillai and Cariappa, 2009
). In vitro experiments have shown that MZ B cells can present CD1d-restricted lipid antigens to invariant (i) NKT cells, although their in vivo contribution to CD1d-restricted antibody responses has not been determined (Barral et al., 2008
; Leadbetter et al., 2008
It is thought that positioning of MZ B cells is dependent on signaling through various G protein–coupled receptors specifically through receptors coupled to Gαi, as treatment of mice with pertussis toxin (PTX), which inhibits all Gαi signaling, leads to a selective loss of B cells from the MZ (Guinamard et al., 2000
). Positioning of MZ B cells is promoted by sphingosine-1-phosphate (S1P), which signals primarily through S1P receptor 1 (S1P1) and, to a lesser extent, through S1P receptor 3 (S1P3) to overcome the follicular attracting activity of the chemokine CXCL13 signaling through its receptor CXCR5 on MZ B cells (Cinamon et al., 2004
). However, in the absence of signaling through both S1P1 and CXCR5, MZ B cells remain positioned within the MZ, in contrast to the loss of MZ B cells after PTX treatment, suggesting that there are additional inputs through receptors coupled to Gαi that mediate positioning of MZ B cells.
The Gαi-coupled cannabinoid receptor 2 (CB2) is expressed in several immune cell types including B cells (Galiègue et al., 1995
). The endocannabinoid 2-arachidonylglycerol (2-AG) is present within the spleen (Sugiura et al., 2006
) and can act as a chemoattractant for mature B cells in vitro (Tanikawa et al., 2007
). Mice deficient for CB2 have fewer MZ B cells than WT mice (Ziring et al., 2006
). However, it is currently unclear whether CB2 deficiency results in defects in MZ B cell development, retention, positioning, or function. Recently it was shown that CB2 promotes retention of immature B cells within BM sinusoids (Pereira et al., 2009a
), raising the question of whether CB2 could also promote cell positioning in the spleen, a possibility which we explored here.