Δ⁹-Tetrahydrocannabinol (THC) Impairs CD8⁺ T Cell-Mediated Activation of Astrocytes.

ABSTRACT: CD8⁺ T cells can contribute to neuroinflammation by secretion of inflammatory cytokines like interferon γ (IFNγ) and tumor necrosis factor α (TNFα). Astrocytes, a glial cell in the brain, can be stimulated by IFNγ and TNFα to secrete the inflammatory cytokines, monocyte chemotactic protein 1 (MCP-1), interleukin 6 (IL-6), and interferon-γ inducible protein 10 (IP-10). Δ⁹-Tetrahydrocannabinol (THC), the primary psychoactive cannabinoid in Cannabis sativa, possesses potent anti-inflammatory activity. The objective of this investigation was to assess the effects of THC treatment on CD8⁺ T cell-mediated activation of astrocytes. CD3/CD28/IFNα- stimulated CD8⁺ T cells were treated with vehicle (0.03% EtOH) or THC and cocultured with U251 astrocytes. IP-10⁺, MCP-1⁺, and IL-6⁺ astrocytes were quantified by flow cytometry. LegendPlex™ was used to measure cytokine secretion by CD8⁺ T cells and flow cytometry was employed to quantify IFNγ, TNFα, and lysosomal-associated membrane protein 1 (LAMP-1) expression. Recombinant TNFα and IFNγ were used to stimulate MCP-1, IP-10, IL-6 responses in U251 astrocytes, which were measured by flow cytometry. Treatment with THC reduced CD8⁺ T cell-mediated induction of IP-10 and IL-6 responses in U251 astrocytes but had no effect on MCP-1. THC treatment differentially affected T cell effector functions such that IFNγ and degranulation responses were sensitive to THC-mediated ablation while TNFα was not. Lastly, THC treatment reduced the IFNγ-induced IP-10 response but had no effect on TNFα-induced MCP-1 response in U251 astrocytes. The results suggest that cannabinoid treatment can selectively reduce certain CD8⁺ T cell responses that contribute to stimulation of astrocytes. Graphical Abstract Treatment with THC can abate CD8⁺ T cell-dependent neuroinflammatory processes by inhibiting CD8⁺ cell differentiation into effector cells, suppressing CD8⁺ effector cell function, and reducing activation of astrocytes by CD8⁺ T cell-derived inflammatory cytokines.

SUBMITTER: Henriquez JE 

PROVIDER: S-EPMC7529688 | biostudies-literature |

REPOSITORIES: biostudies-literature