Effects of targeted deletion of cannabinoid receptors CB 1 and CB 2 on immune competence and sensitivity to immune modulation by Δ 9 ‐tetrahydrocannabinol

The role of cannabinoid receptors, CB 1 and CB 2 , in immune competence and modulation by Δ 9 ‐tetrahydrocannabinol (Δ 9 ‐THC) was investigated in CB 1 −/− /CB 2 −/− mice. Immunofluorescence analysis of splenic leukocytes showed no significant differences in the percentage of T cell subsets, B cells, or macrophages between wild‐type and CB 1 −/− /CB 2 −/− mice. Lymphoproliferative control responses to PHA, phorbol ester plus ionomycin, or LPS and sensitivity to suppression by Δ 9 ‐THC showed no profound differences between the two genotypes, although some differences were observed in control baseline responses. Likewise, similar control responses and sensitivity to Δ 9 ‐THC were observed in mixed lymphocyte responses (MLR) and in IL‐2 and IFN‐γ production in both genotypes. Conversely, humoral immune responses showed a markedly different profile of activity. Δ 9 ‐THC suppressed the in vivo T cell‐dependent, anti‐sheep RBC (anti‐sRBC) IgM antibody‐forming cell (AFC) response in wild‐type but not in CB 1 −/− /CB 2 −/− mice, and the in vitro anti‐sRBC IgM response in CB 1 −/− /CB 2 −/− splenocytes was too low to rigorously assess CB 1 /CB 2 involvement in modulation by Δ 9 ‐THC. Conversely, comparable in vitro IgM AFC control responses to LPS and CD40 ligand (CD40L) activation were observed in the two genotypes. Interestingly, LPS‐induced IgM responses were refractory to suppression by Δ 9 ‐THC, regardless of genotype, and CD40L‐induced IgM responses were only suppressed by Δ 9 ‐THC in wild‐type but not in CB 1 −/− /CB 2 −/− B cells. Collectively, we demonstrate differential involvement of CB 1 and/or CB 2 in immune modulation by Δ 9 ‐THC and in some control responses. Moreover, CB 1 /CB 2 involvement was observed in humoral responses requiring CD40‐initiated signaling for suppression by Δ 9 ‐THC.