Magnitude of stimulation dictates the cannabinoid-mediated differential T cell response to HIVgp120

Abstract

Approximately 25% of immunocompromised HIV patients smoke marijuana for its putative therapeutic benefit. The goal of these studies was to test the hypothesis that marijuana-derived cannabinoids have immunomodulatory effects on HIV antigen-specific T cell effector function. A surrogate mouse model to induce polyclonal T cell responses against HIV(gp120) was established. THC, a marijuana-derived cannabinoid, suppressed or enhanced mouse CD8(+) T cell proliferation and the gp120-specific CTL response depending on the magnitude of the IFN-γ response. To determine the molecular mechanisms by which cannabinoids differentially modulate T cell responses, P/I or anti-CD3/CD28 antibodies were used for stimulation, and another marijuana-derived cannabinoid, CBD, was also investigated. THC or CBD suppressed or enhanced IFN-γ and IL-2 production by mouse splenocytes under optimal or suboptimal stimulation, respectively. Similar differential effects of cannabinoids on cytokine production were also observed on nuclear translocation of NFAT and with human PBMCs in response to P/I stimulation. However, THC and CBD elevated intracellular calcium, regardless of the stimulation level with P/I, suggesting that the cannabinoid-induced calcium increase provides an appropriate signal for activation in suboptimally stimulated T cells but an anergic-like signal as a result of excessive calcium in optimally stimulated T cells. Overall, these data demonstrate differential modulation by cannabinoids of a HIV antigen-specific response and identify a possible mechanism responsible for this effect.

Impaired NFAT and NFκB activation are involved in suppression of CD40 ligand expression by Δ9-tetrahydrocannabinol in human CD4+ T cells

“…It should be noted that the concentrations of Δ 9 -THC used in these studies have not been shown to produce toxicity in mouse or human studies in vitro (Rao et al , 2004; Springs et al , 2008; Chen et al , 2012b). As compared to concentrations found in serum of marijuana users, the concentrations of Δ 9 -THC used in the present studies are higher.…”

Cannabidiol (CBD) and its analogs: a review of their effects on inflammation

“…CBD is generally anti-inflammatory and immuno-suppressive, however under certain conditions, it can elevate cytokine production 57 . Both THC and CBD suppressed or enhanced IFN-γ and IL-2 production by mouse splenocytes under optimal or suboptimal stimulation, respectively.…”

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

“…Specifically, S/o stimulation was defined as 4 nM PMA/0.05 μM Io based on the fact that no IL-2 was produced in response to S/o stimulation alone, and CBD enhanced IL-2 production under these conditions [23]. Initially, this seemed inconsistent with the notion that CBD is anti-inflammatory and immune suppressive [7, 11, 19, 26].…”

“…Second, suboptimal T cell stimulation can be influenced by the presence of optimal stimulation of a distinct antigen, in what has been termed extended antigen priming [22], so studying low-level stimulation in the absence and presence of other antigens is key to understanding complex immune responses. Third, our previous study demonstrated that CBD either inhibited or enhanced IL-2 and IFN-γ production in response to optimal or suboptimal T cell activation, respectively [23], demonstrating that cellular activation dictates the CBD response. We were particularly interested in the consequences of enhanced IL-2 production by CBD in response to low-level T cell activation since IL-2, along with TGF-β1, are key components for inducing and maintaining CD4 + CD25 + FOXP3 + Tregs [24].…”