Abstract

CD4+ T cells enable adaptive immunity to pathogens, notably via cytokine secretion (IL2, IFNy). Cannabidiol (CBD) has been shown to inhibit this secretion. However, with growing evidence suggesting cannabinoids behave biphasically, there is a need to re-evaluate the effect of CBD on CD4+ T cells at a wider range of doses, including the role of CBD’s target receptor, CB2. Additionally, while never investigated in CD4+ T cells, CBD has been shown to moderate clock gene expression (BMAL1, PER2) in other immune cells, which may present an additional mechanism of regulating CD4+ T cell activity. The present study therefore aimed to (1) investigate whether a biphasic dose-response relationship of CBD on CD4+ T cell cytokine expression may exist, (2) whether CB2 activation is biphasic in response to selective stimulation, and (3) whether a biphasic effect on clock gene regulation exists. Primary CD4+ T cells were stimulated in-vitro; CBD or a CB2-selective antagonist (AM630) were incubated at doses ranging 0.001-20 μM. ELISAs were performed to assess cytokine secretion (IL-2, IFNγ); BMAL1 and PER2 gene expression were measured via qPCR. A biphasic trend of cytokine secretion was indeed visualized for most participants, for both drugs. However, the doses at which these trends manifested varied highly across participants and drug vehicle used. No statistically significant, consistent trend was observed for either ELISA nor qPCR data. Still, it is recommended that future studies utilizing these compounds assess effects across a wide range of doses, with special attention to individual differences, vehicles used, and target rhythmicity.