Summary—Cannabinoid receptor activation by agents such as Δ 9 -tetrahydrocannabinol (THC) is known to trigger immune suppression. Here, we show that administration of THC in mice leads to rapid and massive expansion of CD11b+Gr-1+ myeloid-derived suppressor cells (MDSC) expressing functional arginase and exhibiting potent immunosuppressive properties both in vitro and in vivo. The induction of MDSC by THC was associated with a significant increase in granulocyte colony-stimulating factor (G-CSF). Moreover, administration of anti-G-CSF antibody inhibited the induction of MDSC by THC. THC was able to induce MDSC in TLR4 mutant C3H and C57BL10/ScN mice and hence acted independently of TLR4. Accumulation of MDSC in the periphery with a corresponding decrease in the proportion of CD11b+Gr-1+ cells in the bone marrow, as well as in vivo BrdU labeling and cell cycle analysis, showed that THC induced mobilization of these cells from bone marrow and their expansion in the periphery. Use of selective antagonists SR141716A and SR144528 against cannabinoid receptors, CB1 and CB2 respectively, as well as receptor-deficient mice showed that induction of MDSC was mediated through activation of both CB1 and CB2 receptors. These studies demonstrate that cannabinoid receptor signaling may play a crucial role in immune regulation via the induction of MDSC.
