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

Abstract

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 (4 nM/0.05 μM, S/o), ultrasuboptimal PMA/Io (1 nM/0.0125 μM, Us/o) or soluble anti-CD3/28 (400-800 ng 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.

Immune Responses Regulated by Cannabidiol

“…153 We showed in vitro that CBD (1-15 lM) induced functional CD4 + CD25 + Foxp3 + T cells under conditions of suboptimal stimulation and that Il10 mRNA expression was induced. 154 There are only a few studies in which B cells are identified as targets of CBD. CBD given at 25 mg/kg by intraperitoneal (i.p.)…”

“…Indeed, studies from our laboratory and others have shown that CBD either enhanced or suppressed cytokine production (IL-2 and IFN-c) in response to relatively low or high degree of immune stimulation, respectively. 154,179,180 The mechanism for the differential responsiveness likely involves alterations in intracellular calcium, as CBD increases intracellular calcium in mouse splenocytes regardless of the increase of intracellular calcium produced by the immune stimulant. 179 In addition, the differential cytokine production was correlated with nuclear expression of the NFAT transcription factor, 179 which is calcium responsive.…”

“…The second example is IL-2, which was enhanced under conditions of low-level T cell stimulation. 154,179,180 We recently showed that CBD, by producing IL-2 under some conditions, contributed to the appropriate milieu to drive Treg induction, 154 again demonstrating that enhancement of seemingly proinflammatory cytokines by CBD still resulted in immune suppression.…”

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“…[27] Immunomodulatory effects CBD modulated T-cell function and apoptotic signaling pathway. [28] Inflammatory bowel disease (IBD) CBD attenuated intestinal inflammation and normalized motility in patients with IBD. [29] Cognitive impairments CBD interacted with components of emotional memory processing and memory-rescuing, as well as attenuated THC-induced memory impairment effects.…”

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“…Excess PBS was added to stop the enzymatic reaction, and the tissue was minced and meshed on 70 μm filters. Immunofluorescence staining was performed as our previous methods [11]. Briefly, cells were incubated with Fc block solution (purified anti-mouse CD16/CD32, clone 2.4G2, BD Biosciences) for 15 min at room temperature to prevent non-specific binding.…”