Cannabidiol (CBD) induces functional Tregs in response to low-level T cell activation

Many effects of the non-psychoactive cannabinoid, cannabidiol (CBD), have been described in immune responses induced by strong immunological stimuli. It has also been shown that CBD enhances IL-2 production in response to low-level T cell stimulation. Since IL-2, in combination with TGF-β1, are critical for Treg induction, we hypothesized that CBD would induce CD4⁺CD25⁺FOXP3⁺ Tregs in response to low-level stimulation. Low-level T cell stimulation conditions were established based on minimal CD25 expression in CD4⁺ cells using suboptimal PMA/Io (4nM/0.05μM, S/o), ultrasuboptimal PMA/Io (1nM/0.0125μM, Us/o) or soluble anti-CD3/28 (400-800ng each, s3/28). CBD increased CD25⁺FOXP3⁺ cells from CD4⁺, CD4⁺CD25⁺, and CD4⁺CD25^- T cells, as well as in CD4⁺ T cells derived from FOXP3-GFP mice. Most importantly, the Us/o+CBD-induced CD4⁺CD25⁺ Tregs robustly suppressed responder T cell proliferation, demonstrating that the mechanism by which CBD is immunosuppressive under low-level T cell stimulation involves induction of functional Tregs.